TW201023852A - Cancer therapy - Google Patents

Abstract

The present application relates to compositions and methods for treating a proliferative disorder by administering to a subject a pharmaceutical composition of a dual kinase inhibitor. Catecholic butanes cane serve as dual kinase inhibitors for purposes of methods described herein. Subjects can be further treated by co-administering an EGFR inhibitor. The present application also relates to analyzing a sample with respect to levels of IGF-1R and EGFR and comparing levels of IGF-1R and EGFR to a control. Patients can be selected for treatment with a catecholic butane based on the assessment; optionally, patients can be further treated with an EGFR inhibitor, an IGF-1R inhibitor, or both.

Description

201023852 VI. INSTRUCTIONS: This application claims the benefit of U.S. Provisional Application Serial No. 61/112,621, filed on Nov. 7, 2008, which is hereby incorporated by reference in its entirety. A serious threat to modern society. Cancerous growth (including malignant cancerous growth) poses a serious challenge to modern medicine due to its unique characteristics. Features include uncontrolled cell proliferation (which causes, for example, unregulated malignant tissue growth) 'the ability to invade local tissues and even distal tissues, lack of differentiation, lack of detectable symptoms, and most notably effective treatment and prevention. Cancer can be produced in any tissue of any organ of any age. The cause of cancer is not clearly explained, but mechanisms such as genetic susceptibility, chromosomal disruption, and immunological disorders are associated with malignant cell growth and 5L. Cancer encompasses a wide range of medical conditions affecting millions of individuals around the world. Cancer cells can be produced in almost any organ and/or tissue of the body. Cancer occurs when some cells of the body begin to grow or differentiate uncontrolled. All of the cancer types start with uncontrolled growth of abnormal cells. , 'The main available therapies for surgery, radiation therapy and chemotherapy _ surgery, often - severe measures and may have serious consequences. Example ^ All treatments for nest cancer can cause infertility. Cervical cancer and 2 cancers may cause infertility and/or sexual dysfunction. The fishery + procedure may result in partial or total removal of the pancreas 'a significant risk of its own' causing serious side effects to the patient. Breast cancer hand 144535.doc 201023852 Totally involved removal - part or whole breast. Prostate cancer - some surgical procedures have the risk of urinary incontinence and impotence. Procedures for lung cancer patients often have significant post-operative pain because the ribs must be cut to access and remove cancerous lung tissue. In addition, patients with lung cancer and another lung disease (such as emphysema or chronic bronchitis) usually have a rapid increase in breathing after surgery. More than 10 million humans worldwide diagnose cancer every year, and it is estimated that by 2020 this number will become 150,000 new cases per year. Cancer causes 12 〇/〇 of six million deaths or deaths worldwide each year. SUMMARY OF THE INVENTION The embodiments disclosed herein are generally directed to methods of treating diseases using catechol butane or a derivative thereof. Some specific embodiments relate to catechol butyl succinic acid (NDGA) or a salt, solvate, isomer, tautomer, metabolite, analog or prodrug thereof in the treatment of a proliferative disease Use. Provided herein is a method of treating a disease comprising administering an effective amount of a pharmaceutical compound capable of inhibiting the activity of the tyrosine kinase of the insulin-like growth factor-1 receptor (IGF-1R) and the epidermal growth factor receptor (EGFR) (also That is, a dual kinase inhibitor) wherein the pharmaceutical compound is catechol butane. Also provided herein are methods of treating a disease in a subject having resistance to one or more tyrosine kinase inhibitors (eg, one or more EGF-R inhibitors and/or one or more IGF_1R inhibitors) comprising administering an effective amount A pharmaceutical compound (i.e., a single compound of a dual kinase inhibitor) capable of inhibiting the activity of tyrosine kinase of IGF-1R and EGFR, wherein the pharmaceutical compound is catechol butane. 144535.doc 201023852 A disease to be treated using the methods provided herein is a proliferative disease. Proliferative diseases include, but are not limited to, malignant, premalignant or benign cancers. Cancers to be treated using the disclosed methods include, for example, solid tumors, lymphomas, or leukemias. In one embodiment, the 'cancer can be, for example, a brain tumor (eg, a malignant, pre-malignant or benign brain tumor, such as a glioblastoma, astrocytoma, meningioma, a neuroblastoma, or a peripheral neuroectodermal tumor). Carcinoma (eg gallbladder cancer, bronchial carcinoma, basal cell carcinoma, adenocarcinoma, squamous cell carcinoma, small cell carcinoma, large cell undifferentiated carcinoma, adenoma, cystadenoma, etc.), basal cells Tumor (basaii〇rna), teratoma, retinoblastoma, choroidal melanoma, seminoma, sarcoma (eg Ewing sarcoma, rhabdomyosarcoma, pharyngeal tumor, osteosarcoma, chondrosarcoma, Muscle, liposarcoma, fibrosarcoma, leiomyosarcoma, Askin's tumor, lymphosarcoma, neurosarcoma, Kaposi's sarcoma, cutaneous fibrosarcoma, angiosarcoma, etc., plasmacytoma , head and neck tumors (such as mouth, throat, nasopharynx, esophagus, etc.), liver tumors, kidney tumors, renal cell tumors, squamous cell carcinoma, uterine tumors, bone tumors , prostate tumors, breast tumors (including but not limited to breast tumors of Her2- and / or ER- and / or PR-tumor), bladder tumors, pancreatic tumors, endometrial tumors, squamous cell carcinoma, stomach tumors , glioma, colorectal tumor, testicular tumor, colon tumor, rectal tumor, ovarian tumor, cervical tumor, ocular tumor, central nervous system tumor (eg primary CNS lymphoma, spinal tumor, brain stem glioma) , pituitary adenomas, etc.), thyroid tumors, lung tumors (such as non-small cell lung cancer (NSCLC) or small cell lung cancer), leukemia or lymphoma (eg 144535.doc 201023852 such as cutaneous T-cell lymphoma (CTCL), non-skin peripheral T-cell lymphoma, lymphoma associated with human T-cell lymphotrophic virus (HTLV) (such as adult T-cell leukemia/lymphoma (ATLL)), B-cell lymphoma, acute non-lymphocyte White king disease, chronic lymphocytic leukemia, chronic myelogenous leukemia, acute myeloid leukemia/lymphoma and multiple myeloma, non-Hodgkin's lymphoma non-Hodgkin lymphoma), acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), Hodgkin's lymphoma, Burkitt lymphoma, adult T-cell leukemia/ Lymphoma, acute myeloid leukemia (AML), chronic myelogenous leukemia (CML) or hepatocellular carcinoma, etc., multiple myeloma, skin tumors (eg basal cell carcinomas, squamous cell carcinoma, melanoma) (such as malignant melanoma, cutaneous melanoma or intraocular melanoma), protuberous cutaneous fibrosarcoma, Merkel cell carcinoma or Kaposi's sarcoma, gynecological tumors (eg uterine sarcoma, fallopian tube cancer, Endometrial cancer, cervical cancer, vaginal cancer, vaginal cancer, etc.), Hodgkin's disease, small bowel cancer, endocrine cancer (such as sputum, parathyroid or adrenal cancer), Skin tumor, urethral cancer, penile cancer, tumor associated with Gorlin's syndrome (eg, neuroblastoma, cerebral ridge) Ependymoma, etc.), tumors of unknown origin; or either one of metastases. In another embodiment, the cancer is a lung tumor, a breast tumor, a colon tumor, a colorectal tumor, a head and neck tumor, a liver tumor, a prostate tumor, a glioma, a glioblastoma multiforme, an ovarian tumor or a goiter 144535 .doc 201023852 Tumor; or metastases of either. In another embodiment, the cancer is an endometrial tumor, a bladder tumor, multiple myeloma, melanoma, renal tumor, sarcoma, cervical tumor, leukemia, and neuroblastoma. The tumor provided herein can be a primary tumor or a metastatic tumor. Proliferative diseases can also be skin conditions. In one aspect, the skin condition is, for example, a tumor, actinic keratosis, acne, psoriasis, skin wounds, sputum, bacterial infection, fungal infection, or viral infection. Viral infections include, but are not limited to, HI V infection, HP V infection, or HSV infection. Provided herein are methods of treating malignant, pre-malignant or benign cancer comprising administering an effective amount of a pharmaceutical compound (i.e., a single compound that is a dual kinase inhibitor) capable of inhibiting the activity of tyrosine kinase of IGF_1R and EGFR, wherein the medicament The compound is catechol butane. Cancers to be treated using the disclosed methods include, for example, solid tumors, lymphomas, or leukemias. In one embodiment, the cancer can be, for example, a brain tumor (eg, a malignant, pre-malignant or benign brain tumor, such as a glioblastoma, astrocytoma, a meningomoma, a neuroblastoma, or a peripheral neuroectoderm) Tumor), carcinoma (eg gallbladder cancer, bronchial carcinoma, basal cell carcinoma, adenocarcinoma, squamous cell carcinoma, small cell carcinoma, large cell undifferentiated carcinoma, adenoma, cystadenoma, etc.), base Baccaroma (basali〇ma), teratoma, retinoblastoma, seminoma, sarcoma (eg Ewing's sarcoma, rhabdomyosarcoma, craniopharyngioma, osteosarcoma, chondrosarcoma, myoma, liposarcoma, fiber Sarcoma, leiomyosarcoma, Askin's tumor, 144535.doc 201023852 Lymphosarcoma, nerve (4), Kaposi's sarcoma, cutaneous fibrosarcoma, angiosarcoma, etc.), plasmacytoma, head and neck tumors (eg mouth, throat, Nasopharyngeal, esophageal, etc.), liver tumor, kidney tumor, renal cell tumor, squamous cell carcinoma, uterine tumor, bone tumor, prostate tumor, breast tumor (including but not limited to ) is Her2- and / or ER- and / or PR-tumor breast tumors), bladder tumors, pancreatic tumors, endometrial tumors, squamous cell carcinoma, stomach tumors

Glioma, colorectal, testicular, colon, rectal, ovarian, cervical, ocular, central nervous system (eg primary CNS lymphoma, spinal tumor, brainstem glioma, Pituitary adenomas, etc., squamous adenocarcinoma, lung tumors (such as non-small cell lung cancer (NSCLC) or small cell lung cancer), leukemia or lymphoma (such as skin tau cell lymphoma (CTCL), non-skin peripheral tau cell lymphoma Lymphoma associated with pro-human tau cell lymphovirus (HTLV) (such as adult tau cell leukemia/lymphoma (ATLL)), B-cell lymphoma, acute non-lymphocytic leukemia, chronic lymphocytic leukemia, chronic myelositosis Leukemia, acute myeloid leukemia/lymphoma and multiple osteosarcoma, non-Hodgkin's lymphoma, acute lymphocytic leukemia (all), chronic lymphocytic white disease (CLL), Hodgkin's lymphoma, Bo Kitt lymphoma, adult tau cell leukemia/lymphoma, acute myeloid leukemia (AML), chronic myelogenous leukemia (CML) or hepatocellular carcinoma, etc. Myeloma, skin tumors (such as basal cell carcinomas, squamous cell carcinoma, melanoma (such as malignant melanoma, choroidal melanoma, cutaneous melanoma or intraocular melanoma), protuberant skin fibers Sarcoma, Merkel cell carcinoma or Kaposi's sarcoma, gynecological neoplasms (eg 144535.doc 201023852 uterine sarcoma, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, genital cancer, etc.) , Hodgkin's disease, small bowel cancer, endocrine cancer (such as thyroid gland, parathyroid or adrenal cancer), mesothelioma, urethral cancer, penile cancer, tumors associated with Golling's syndrome (eg neural tube Tumors, hematopoietic membranes, etc.), tumors of unknown origin; or metastases of either. In another embodiment, the cancer is a lung tumor, a breast tumor, a colon tumor, a colorectal tumor, a head and neck tumor, a liver tumor, a prostate tumor, a glioma, a glioblastoma multiforme, an ovarian tumor, or a thyroid tumor; Or a metastasis of either. In another embodiment, the cancer is an endometrial tumor, a bladder tumor, multiple bone tumors, melanoma, renal tumor, sarcoma, cervical tumor, leukemia, and neuroblastoma. The tumor provided herein can be a primary tumor or a metastatic tumor. Cancer can also be epithelial-based cancer. In one embodiment, the tumor cells can exhibit EGFR. In another embodiment, the tumor cells can exhibit IGF1R. In another embodiment, the tumor cells can exhibit EGFR and IGF-1R. Provided herein are methods of treating a skin condition comprising administering an effective amount of a pharmaceutical compound (i.e., a single compound that is a dual kinase inhibitor) capable of inhibiting the activity of tyrosine kinase of IGF-1R and EGFR, wherein the pharmaceutical compound is Sterol butane. In one aspect, the skin condition is, for example, a tumor, actinic keratosis, acne, psoriasis, skin wounds, sputum, bacterial infection, fungal infection, or disease Z infection. Viral infections include, but are not limited to, HIV infection, Hcv infection, 144535.doc •10-201023852 HBV infection, HPV infection, and HSV infection. Skin tumors include, but are not limited to, basal cell carcinomas, squamous cell carcinoma, melanoma, hyperplastic cutaneous fibrosarcoma, Merkel cell carcinoma, and Kaposi's meat. The pharmaceutical composition administered by the individual is catechol butadiene. In one embodiment of the methods described herein, the catechol butane may have the structure of:

Wherein R! and R2 are independently hydrazine, lower alkyl or lower fluorenyl; R3, R4 'R5 'R6, R1, R11, Rl2 and R13 are independently hydrazine or lower alkyl; and R?, Rs and R9 are independently a hydrazine, a hydroxyl group, a lower alkoxy group or a lower carbon anthracene Φ group. Also included are pharmaceutically acceptable salts of Formula 1, pharmaceutically acceptable solvates 'tautomers, metabolites, and prodrugs. In another embodiment of the methods described herein, the catechol butane may have the structure of Formula II:

Wherein Κ·5, R10, R6 and R13 are independently Η; 144535.doc -11 - 201023852 When Tian Han 3 is Η, RU is a lower alkyl group; or when r3 is a lower alkyl group, Rn is Η; When R4 is Η, ft ^ ^ ^ is lower alkyl; or when ft 4 is lower alkyl, r12 is Η; R7 Rs and R_9 are both hydroxyl and η, and relative to stretching An alkyl substituent having one hydroxyl group at the 3 position and another hydroxyl group at the 4 position. Also included are pharmaceutically acceptable salts of the formula II, pharmaceutically acceptable solvates, tautomers, metabolites and prodrugs. Non-limiting examples of the catechol butane used in the method of the present invention include, for example, NDGA, tetra-indole methyl NDGA; tetraglycol aryl ndga; tetra-diglycidyl fluorenyl NDGA or a salt thereof; 〇 〇 曱 ND NDGA; n-dihydroguaiare acid tetrapivalate, n-dihydroguaiac acid tetrapropionate and all its optical configurations. Non-limiting examples of catechol butanes useful in the process of the invention also include, for example, M-bis(3,4-dihydroxyphenyl)_2,3-didecylbutane; 14 bis(34-dihydroxybenzene) Butane; 1,4-bis(3,4-dimethoxyphenyl)_2,3-dimethylbutane, 1,4-bis(3,4-diethoxyphenyl)_2 , 3-dimercaptobutylate; 14_bis(3,4-propoxyphenyl)-2,3-dimercaptobutylate; i (3,4-di-phenyl)-4 -(3,4,5-trihydroxyphenyl)butane; 1,4-bis(3,4-diethoxyoxyphenyl)_ 2,3-methylbutane, 1,4-double (3,4-dipropenyloxyphenyl)_2,3-dipyridinane; 1,4-bis(3,4-dibutoxyphenyl)·2,3·dimethylbutane Calcined; hydrazine, 'bis(3,4·dipentyloxyphenyl)-2,3-didecylbutane; di-tertyloxycarbonyl)-2,3-monomethylbutanthene; , 4-bis(3,4-diopenopenylphenyl)-2,3-dimethylbutane; or 1-(3,4-dihydroxyphenyl)-4-phenylbutene 144535. Doc 12 201023852 alkane; and 1-(3,4-dihydroxyphenyl)_4, violent) d-isomer, 1-isomer of 4-(2,5-dihydroxyphenyl)butane, D-异礼w Wu and U isomers Racemic mixtures and racemic isomers. In one embodiment, the catechol guanidine helmet j pit is n-dihydroguaiac acid (NDGA). The medicine of the embodiment of the invention and a from forging, sigma can be formulated for any administration route, such as intranasal administration; oral administration ^ ^ ^ ^ ^ ^ ^ ^ 1 m, inhalation, subcutaneous administration ;through

f peony, intra-arterial administration, with or without obstruction; intracranial administration, intra-medication, intravenous administration; intra-frequency administration; intraperitoneal administration; intraocular drug, intramuscular administration, implanted; And central vein administration. In one embodiment, catechol butane is formulated for oral administration. In another embodiment, catechol butane is formulated for intravenous administration. The dosage of catechol butane can be determined empirically. By way of example only, catechol butane may be from about 5 mg/kg to about 375 mg/kg per dose; from about 5 mg/kg to about 250 mg/kg per dose; from about 5 mg/kg to about 200 mg per dose. /kg; from about 5 mg/kg to about 150 mg/kg per dose; from about 5 mg/kg to about 1 mg/kg per dose; from about 5 mg/kg to about 75 mg/kg per dose; or per dose It is administered in an amount of from about 5 mg/kg to about 50 mg/kg. Alternatively, the catechol butane may be administered from about 1,500 mg per day to about 2,500 mg per day; from about 1,800 mg per day to about 2,300 mg per day; or about 2,000 mg per day. In one embodiment, the catechol butane can be contacted with the target cells at a concentration ranging from about 1 μΜ to about 30 μΜ. In another embodiment, the catechol butane can be contacted with the target cells at a concentration ranging from about 1 μΜ to about 1 μ μΜ. In one embodiment, the pharmaceutical composition may be administered more than once per 6 days for a period of time, or once every 2 weeks for a period of time. In the case of a real 144535.doc •13- 201023852, daily vote. The matter lasted four weeks. In another example, the pharmaceutical composition was administered three times a day for two weeks, with a one-week break before the start of the new cycle. In another example, the pharmaceutical composition was administered for one week and then interrupted for one week. In any other embodiment, the pharmaceutical composition is administered daily for two weeks and then discontinued for two weeks. In another embodiment, each medicinal composition is administered once or twice a person's or one week prior to the start of a new cycle. In another embodiment J Ύ The pharmaceutical composition is administered once a week or twice a week. In any of the methods provided herein, the individual administered to the catechu can be improved by a variety of other anticancer agents or therapeutic therapies. Anticancer agents include, but are not limited to, DNA disrupting agents. In some embodiments, the anti-cancer inhibitor and the silk fibrosis may be an EGFR inhibitor, an IGIMR inhibitor, or both. In the aspect of the method described herein, the patient who is administered with catechin can be further inhibited by administering EGFR inhibition, and IGF_1R inhibition! Or both treatments 0 In one embodiment, the individual to be treated may be administered with one or more tyrosine kinase inhibitors (eg, only EGFR inhibitors, only IGF, 1R inhibitors or egfr inhibitors and IGF-1R inhibitors) The treatment is resistant. Provided herein are methods for screening individuals for levels of IGF-1R and EGFR tyrosine kinase activity comprising: (1) analyzing a sample obtained from an individual comprising measuring the amount of IGF-1R and EGFR; and (ii) placing the sample in the sample The contents of IGF1R and EGFR were compared with those in the control group. Provided herein are methods for determining disease therapy comprising: (1) analyzing a sample obtained from an individual 144535.doc •14-201023852, which comprises measuring the levels of IGF-1R and EGFR, and (ii) placing IGF-1R and EGFR in the sample. The amount is compared with the amount in the control group; wherein an increase in the content of IGF-1R, EGFR or both compared to the control group indicates that the individual is to use a dual tyrosine kinase inhibitor (ie, inhibiting IGF-1R and EGFR). Single compound) treatment. In one embodiment, the dual tyrosine kinase inhibitor is a catechol butane such as described herein. In one embodiment, the EGFR expression is at or above baseline and the IGF-IR performance is baseline or exceeds baseline. In another embodiment, the amount of EGFR expression is baseline and the amount of IGF-1R expression is 2 or more times the baseline content. In another embodiment, the IGF-IR performance is baseline and the EGFR expression is 2 or more times the baseline level. In another embodiment, the IGF-1R expression is 2 or more times the baseline level and the EGFR expression is 2 or more times the baseline level. The messenger RNA (mRNA) levels of IGF-1R and EGFR can be analyzed by using assays such as reverse transcriptase-polymerase bond reaction (RT-PCR), Northern hybridization, in situ hybridization, and quantification of rt_pcr (qRT). -PCR) 0 The protein content of IGF-1R and EGFR can be analyzed using the following assays: such as enzyme-linked immunosorbent assay (ELISA), Western blot, immunohistochemistry, immunoprecipitation, immunofluorescence, enzyme immunoassay (EIA) And radioimmunoassay (RIA). The genomic DNA content of IGF-1R and EGFR can be determined using, for example, Southern hybridization or gene chip analysis. In one aspect, 'IGF-1R and EGFR can be analyzed by the following steps. (4) 144535.doc -15- 201023852 Introducing labeled antibodies against IGF-1R and labeled antibodies against EGFR' and (b) The labeled antibodies are detected by standard imaging techniques. The antibody can be labeled with a radioactive label whose presence and location in the individual can be measured by standard imaging techniques. In one embodiment, the radiolabeling of the antibody against IGF-1R and the antibody against EGFR is different. In one aspect, the method may further comprise administering to the individual a pharmaceutical compound capable of inhibiting tyrosine kinase activity of IGF-1R and EGF-R, wherein the pharmaceutical compound is a catechin inhibiting IGF-1R and EGFR Burn (i.e., dual kinase inhibitor). In any of the methods provided herein, one or more additional anticancer agents and/or therapeutic therapies can be further administered to the individual. Anticancer agents include, but are not limited to, DNA disrupting agents, topoisomerase inhibitors, and mitotic inhibitors. In one embodiment, the one or more anticancer agents can be an EGFR inhibitor, an IGF-1R inhibitor, or both. In one aspect of the methods described herein, the patient can be further treated by administering an EGFR inhibitor, an IGF-IR inhibitor, or both. In one embodiment, the individual to be treated may be resistant to treatment with an EGFR only inhibitor, only an IGF-IR inhibitor or an EGFR inhibitor, and an iGF_inhibitor. In one aspect, the individual to be treated has the above proliferative disease. Provided herein are methods of selecting an individual for treatment with catechol butane (i.e., a dual kinase inhibitor) capable of inhibiting the tyrosine kinase activity of IGF_1R and EGF-R, wherein the individual is identified as possessing IGF_1R, EGFR, or both The content of the substance was twice the baseline content or the baseline content compared with the control group. In one aspect, the individual has previously been treated with an EGFR inhibitor or IGF-IR inhibitor 144535.doc -16-201023852. In another aspect, the individual may be resistant to treatment with at least one tyrosine kinase inhibitor (e.g., an EGFR inhibitor and/or an IGF-IR inhibitor). In one aspect, the pharmaceutical composition to be administered to an individual is catechol butane. The route, dosage and schedule of catechol butane are as described above. • In any of the methods provided herein, one or more additional anticancer agents and/or therapeutic therapies may be further administered to the individual. Anticancer agents include, but are not limited to, DNA disrupting agents, topoisomerase inhibitors, and mitotic inhibitors. ® In one embodiment, the one or more anticancer agents to be administered are an EGFR inhibitor, an IGF-1R inhibitor, or both. In one aspect of the methods described herein, the patient can be further treated by administering an EGFR inhibitor, an IGF-IR inhibitor, or both. In one embodiment, the individual to be treated may be resistant to treatment with at least one tyrosine kinase inhibitor (e.g., only an EGFR inhibitor, only an IGF-IR inhibitor or an EGFR inhibitor and an IGF-IR inhibitor). A In one aspect, the individual (patient) to be treated has a proliferative disease, such as

W The proliferative disease described herein. In one embodiment, the EGFR expression is at or above baseline and the IGF-IR performance is baseline or exceeds baseline. In another embodiment, the EGFR expression is baseline and the IGF-1R performance is 2 or more times the baseline content. In another embodiment, the IGF-IR performance is baseline and the EGFR expression is 2 or more times the baseline level. In another embodiment, the IGF-1R expression is 2 or more times the baseline level and the EGFR expression is 2 or more times the baseline level. 144535.doc • 17· 201023852 [Embodiment] All publications mentioned in the specification are hereby incorporated by reference, the entireties of each of The degree is as if the individual publications, patents or patent applications have been specifically and individually incorporated by reference. The novel features of the embodiments are set forth in the appended claims. The features and advantages of the embodiments of the invention are set forth in the <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; DEFINITIONS The above summary of the invention is to be considered as illustrative and not restrictive. In the present application, the use of the singular includes the plural unless otherwise specified. It must be noted that the singular forms "a" and "the" It should also be noted that the use of "or" means "and / or" unless otherwise stated. Moreover, the use of the term "comprising" is not limiting. By "solid tumor" is meant a tumor in which a plurality of tumor cells are bound to each other&apos;, i.e., adjacent to each other and within a restriction site. It is in contrast to "fluid" or "hematogenous" tumors in which tumor cells are predominantly present in non-associated or individual cell forms, such as leukemia. Solid tumors are usually found in host tissues such as epithelial tissues, connective tissues, and supporting tissues, as well as other tissues located throughout the body. "Surgery" means any treatment or diagnostic procedure involving the hand or hand and the systemic effects of the instrument on the human or other mammalian body to produce a therapeutic, remedy or diagnostic effect. /σ "Radiation therapy" means exposing a patient to high-energy radiation, including but not limited to xenon rays, gamma rays, and neutrons. Such therapies include, but are not limited to, external-beam therapy, internal radiation therapy, transplant radiation, 0 proximity radiation therapy, systemic radiation therapy, and radiation therapy. "Chemotherapy" means the administration of one or more cancer patients by various methods including intravenous, oral, intramuscular, intraperitoneal intravesical, subcutaneous, transdermal, buccal or inhalation or in the form of suppositories. Anticancer drugs, such as anti-neoplastic chemotherapeutics, chemopreventive agents, and/or other agents. Chemotherapy can be administered prior to surgery to reduce large tumors and subsequent surgical procedures to remove them, either after surgery or radiation therapy to prevent the growth of any remaining cancer cells in the body. φ The term "effective amount" or "pharmaceutically effective amount" means an amount of a drug that is non-toxic but sufficient to provide the desired biological, therapeutic, and/or prophylactic effect. The result may be to reduce and/or alleviate the signs, symptoms or causes of the disease or any other desired changes in the biological system. For example, an &quot;effective amount&quot; for therapeutic use is the amount of the catechol butane itself disclosed herein or a composition comprising the catechol butane herein to provide a significant reduction in the treatment of the disease. The appropriate effective amount in any individual case can be determined by routine experimentation by those of ordinary skill in the art. "Pharmaceutically acceptable" or "pharmacologically acceptable" means that the substance is not 144535.doc 19- 201023852 may be biologically or otherwise unsuitable, that is, the substance may be administered to the individual without causing any It is not suitable for biological effects or interacts in a detrimental manner with any component of the composition containing the substance. The term "treatment" as used herein and its grammatical equivalent terms include achieving a therapeutic benefit and/or a prophylactic benefit. Therapeutic benefit means eradication or amelioration of the underlying condition being treated. Treatment also refers to obtaining the desired pharmacological and/or physiological effects. The effect may be prophylactic and/or may partially or completely cure the condition or disease and/or may be attributable to the adverse effects of the condition or disease in terms of completely or partially preventing the condition or disease or its symptoms. In other words, this effect can be therapeutic. Thus, "treating" is, for example, any treatment that covers the condition or disease of a mammal, especially a human, and includes: (4) preventing the development of the condition in an individual who may be susceptible to the condition or disease but has not yet been diagnosed as having the condition or disease. Or disease; (b) inhibiting the condition or disease, such as preventing its development; and (4) mitigating, alleviating or ameliorating the condition or disease, such as causing the condition or disease to subside. By way of example only, in the case of cancer φ 去 正 / 正 w, therapeutic benefit may include eradication or improvement of underlying cancer. The treatment benefit can also be achieved by eradicating or ameliorating one or more of the physiological symptoms associated with the underlying condition such that an improvement can be observed in the patient, but the patient may still suffer from the underlying condition. For a prophylactic benefit, a patient who has a risk of developing cancer or a patient who reports one or more physiological symptoms of the condition but has not yet diagnosed the condition may perform a method or a combination of administration to the patient. + 畀β In some cases, treatment means stagnation (even if the disease does not worsen) and prolongs the patient's survival. The dosage to be administered depends on the individual to be treated, such as the general health of the individual, the condition of the age of the individual, the size of the individual, and the size of the tumor. 144535.doc •20· 201023852 “The term “individual”, “individual” or “individual” as used in relation to an individual suffering from a condition and its similar expression encompasses mammals and non-mammals. Examples of mammals include, but are not limited to, any member of the dairy animal category, humans, non-human primates such as black (four), and other post-and monkey species; farm animals such as cattle, horses, sheep, goats, pigs Livestock, such as rabbits, dogs, and cats; experimental animals' include rodents such as rats, mice, and guinea pigs, and the like. Examples of non-mammals include, but are not limited to, birds 'fish and their similar non-spray animals. In some embodiments of the methods and compositions provided herein, the mammal is a human. The terms "co-administered", "combined with administration", and grammatically equivalent terms or the like, as used herein, are intended to encompass a single-patient administration of a selected therapeutic agent, and are intended to include the following therapeutic therapies, wherein The agents are administered by the same or different routes of administration or at the same or different times. In some embodiments: the inhibitor is co-administered with other agents. These terms encompass the administration of two or more scorpions to an animal to allow both agents and/or their metabolites to be present in the animal simultaneously. It includes simultaneous administration as a separate composition, administration in separate compositions at different times, and/or administration in the presence of a combination of the two agents. Thus &apos;in some embodiments&apos; inhibitors and other agents are administered as a mono-composition. In some embodiments, &apos;inhibitors and other agents are mixed in the composition. In other embodiments, the inhibitor and other agents are administered at separate doses in separate doses. The term "pharmaceutical composition" as used herein refers to a biologically active compound that is optionally mixed with at least one pharmaceutically acceptable chemical component such as, but not limited to, a carrier, a stabilizer, Diluent, 144535.doc 201023852 Powder, suspending agent, thickener and / or excipients. The term "carrier" as used herein, refers to a relatively non-toxic compound or agent that facilitates the incorporation of a compound into a cell or tissue. The term "pharmaceutically acceptable excipient" includes vehicles, adjuvants or diluents or other auxiliary substances, such as those well known in the art, which are readily available to the public. For example, pharmaceutically acceptable adjuvant materials include pH adjusting and buffering agents, tonicity adjusting agents, stabilizers, wetting agents, and the like. The term "metabolite" as used herein refers to a derivative of a compound which is formed upon metabolism of the compound. The term "active metabolite" as used herein refers to a biologically active derivative of a compound which is formed upon metabolism of the compound. As used herein, the term "metabolism" refers to a summary of the process by which a particular substance is altered by an organism, including but not limited to hydrolysis and enzymatic reactions. Thus, the enzyme can produce specific structural changes to the compound. For example, cytochrome P450 catalyzes a variety of oxidation and reduction reactions, while uridine dihydroglucose-transferase catalyzes the activation of glucuronic acid molecules into aromatic alcohols, aliphatic alcohols, carboxylic acids, amines, and Free sulfhydryl. Additional information on metabolism can be obtained by The Pharmacological Basis 〇f Therapeutics, 9th edition, McGraw-Hill (1996). The term "unit dosage form" as used herein refers to a single unit of physical individual unit suitable for use as a human and animal subject, each unit containing a predetermined amount of API calculated to produce the desired effect, and a pharmaceutically acceptable diluent. , carrier or vehicle. The specifications of the novel unit dosage forms of the compounds of the invention depend on the particular compound employed and the effect to be achieved, and the efficacy of each compound in the subject of 144535.doc -22. 201023852. As used herein, "percent" or the symbol "%" means weight/weight (w/w), weight/volume (w/v) 戋 volume/volume (v/) based on the amount of vehicle present in the composition. v) The percentage of the components specified in the composition, as indicated by any particular component, is based on the amount of carrier present in the composition. Thus, as indicated, different types of carriers can be present in amounts up to 100%, which does not exclude the presence of API, and the amount of API can be specified as a percentage (%) or a specific number of milligrams present in the composition. (mg), or the specific number of milligrams (mg/mL) present per ml, of which the total amount of carrier present in the %4 mg/mUx composition is calculated. A particular type of carrier can be present in combination to form 100°/. Carrier. A "substantially pure" compound for a catechol butane or NDGA compound or derivative is a compound which does not substantially contain a substance other than a catechol butane, an NDGA compound or an NDGA derivative. By way of example, it does not mean that at least about 50% of the non-NDGA material is at least about 7%, at least about 80%, at least about 90% free, or at least about 95% free of non-ndga species. The term "tumor cell antigen" is defined herein as an antigen present in a higher amount on a tumor cell or in a body fluid than in an unrelated tumor cell, normal cell or normal body fluid. The presence of antigen 乂 can be determined by a number of assays known to those skilled in the art, including, but not limited to, antibody negative and/or positive selection, such as ELISA assays, radioimmunoassays, or by Western blotting. A gamma cell apoptosis inducing agent is defined herein as inducing apoptosis/progressive, w cell death, and includes, for example, an anticancer agent and a cell (eg, a tumor cell) 144535.doc -23-201023852 Progressive cell death therapy. Exemplary apoptosis inducers are described in more detail below. The term "apoptosis" or "progressive cell death" refers to a physiological process in which harmful or unwanted cells are removed from the physiological process during development and other normal biological processes. Apoptosis is a pattern of cell death under normal physiological conditions, and the cell is an active participant in its own death ("cell suicide"). It is most often found during normal cell renewal and tissue constant state, embryogenesis, induction and maintenance of immune tolerance, nervous system development and endocrine dependence! Apoptotic cells display unique morphological and biochemical features. These features include chromatin accumulation, nuclear and cytoplasmic cytoplasmic nucleus, and nuclear distribution in membrane-bound vesicles (cells). These membrane-bound vesicles contain ribosomes, morphologically intact mitochondria, and nuclear material. In vivo, these apoptotic bodies are rapidly recognized and phagocytosed by macrophages, dendritic cells or adjacent epithelial cells. Due to this effective mechanism for removing dead cells in vivo, no inflammatory response is induced. In vitro, the apoptotic bodies as well as the remaining cell fragments eventually swell and eventually dissolve. This terminal phase of in vitro cell death is called "secary ndary © necrosis". Apoptosis can be measured by methods known to those skilled in the art, such as DNA fragmentation, phospholipid binding protein V exposure, caspase activation, cytochrome e release, and the like. The cells that have been induced to die are referred to herein as "apoptotic cells." - Cell death can also be tested using the following standard phospholipid binding protein V cell apoptosis assay: NlH: 〇VCAR-3 cells are grown in 6-well plates (NUNC) and irradiated or with an antagonist (or with another anti-cancer) The drug combination) was treated for 4 to 48 hours, washed 144535.doc -24·201023852 and stained with the fat-binding protein V-FITC (BD-Pharmingen) for 1 hour. The cells were analyzed by flow cytometry (Becton-Dickinson, CellQuest), stained with propidium iodide, and analyzed by flow cytometry. Catechol Ding Hyun As used herein, the term "catechol butane" refers to a compound that is a dual kinase inhibitor of EGFR and IGF-1R (i.e., a single compound that acts as a dual kinase inhibitor). In one embodiment, the catechol butane may have the structure of Formula I:

Wherein Ri and R2 are independently H, lower alkyl or lower fluorenyl; r3, R4, R5, R6, R1(), Rn, R12 and R丨3 are independently hydrazine or a lower carbon group; and R7 And Rs and R9 are independently hydrazine, a mercapto group, a low carbon alkoxy group or a lower carbon methoxy group. Also included are pharmaceutically acceptable salts of formula I, pharmaceutically acceptable solvates, tautomers, metabolites and prodrugs. In another embodiment, the catechol butane may have the structure of Formula II:

R9 Rs wherein R5, Rio, R6 and Rl3 are independently Η; when R3 is Η, Rn is lower alkyl; or when R3 is lower alkyl, 144535.doc -25- 201023852 R11 is Η, 菖When R4 is ruthenium, Ri2 is a low carbon alkyl group; or when r4 is a low carbon alkyl group, R12 is ruthenium, two of R7, Rs and R9 are hydroxyl groups, and the other is ruthenium, and relative to the stretching group Substituents, - the radical is in the 3 position, and the other is in the 4 position. Also included are pharmaceutically acceptable salts of the formula II, pharmaceutically acceptable solvates, tautomers, metabolites and prodrugs. Lower alkyl as used herein is intended to mean Ci_C6 alkyl, and preferably is 114 and Ci-C3 alkyl. Lower alkyl as used herein also especially denotes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl tert-butyl, n-pentyl, isopentyl, n-hexyl and the like. Group. The low carbon fluorenyl group as used herein is intended to generally mean a [Ci_C6] fluorenyl group, wherein the [C2-C6] fluorenyl group is preferred. The low carbon fluorenyl group as used herein also means a group having the formula RCO- such as ethionyl group, propyl fluorenyl group (CHsCHKO-), butyl fluorenyl group (chchkj^co), and the like. The catechu is expected to be a phenolic compound and its conventional esters and ethers. When the catechin compound is, for example, a substituted phenyl group, the corresponding groups are ethoxycarbonyl (CH3C〇2—), propenyloxy (CH3CH2C〇2—) and butanoxy (CH3CH2CH2C〇2 — ). The compound may be a single optical isomer or a mixture of such isomers (e.g., a racemic mixture) or a diastereomeric form. In the examples, the catechu is calcined as n-dihydroguaiac acid (NDGA) or a derivative thereof. The di-n-argon-guaiac acid is a phenolic compound identified as the main component of tea's resin extraction from the creosote bush Chaparral oak 144535.doc • 26- 201023852 (Zarrea mountain vahca/ia) Preparation. Non-limiting examples of catechol butanes useful in the methods of the invention include, without limitation, NDGA, tetra-indenyl-fluorenyl NDGA; tetraglycine fluorenyl NDGA; tetra-dimethylglycol fluorenyl NDGA or a salt thereof; and a tris-methyl group&gt; 〇3 (} octane; n-dihydroguaiare acid tetrapivalate; n-dihydroguaiare acid tetrapropionic acid vinegar and all optical configurations thereof. Non-limiting examples of catechol butane also include, for example, 1,4-bis(3,4-dihydroxyphenyl)-2,3-dimethylbutane; hydrazone bis-dihydroxyphenyl) Butane; 1,4-bis(3,4-dimethoxyphenyl)_23-dimethylbutane, 1,4-bis(3,4-diethoxyphenyl)-2,3- Dimethyl butyrate; 1,4_bis(3,4-dipropoxyphenyl)-2,3-dimethylbutane; 1-(3,4-di-phenyl)-4- (3,4,5-trihydroxyphenyl)butane; 1,4-bis(3,4-diethoxymethoxyphenyl)-2,3-didecylbutane; 1,4-double ( 3,4-dipropenyloxyphenyl) 2,3-dimethylbutane; M-bis(3,4-dibutoxyphenyl)-2,3-dimethylbutane; (3,4-dipentyloxyphenyl)-2,3-dimethylbutane; 1,4-bis(3,4-di-tertyl milk base) Benzyl-2,3-dimercaptobutyrate; 1,4-bis(3,4-dipentyl ethylphenyl)-2,3-dimethylbutane; or 1-(3,4 -di-p-phenyl)-4-phenylbutane; and the d-isomer of 1-(3,4-dihydroxyphenyl)-4-(2,5-dihydroxyphenyl)butane, 1-isomeric, d-isomer, and 1-isomer racemic mixture and meso isomer. Other catechol butanes described in this technology are contemplated for use herein. For example, U.S. Patent No. 5,008,294; U.S. Patent No. 6,291,524; or U.S. Patent No. 6,417,234; U.S. Published Application No. 20080207532, No. 20080096967, No. 20060151574, No. 20060141029, and 144535.doc -27-201023852 No. 20070099847 The catechol butane is incorporated herein by reference. The definitions of standard chemical terms can be found in references (including Carey and Sundberg, "Advanced Organic Chemistry 4th Edition", Volume A (2000) and Volume B (2001), Plenum Press, New York). Unless otherwise stated, mass spectrometry, NMR, HPLC, IR and UV/Vis spectroscopy and conventional methods of pharmacology in this technique are used. Unless specific definitions are provided, the names used in analytical chemistry, synthetic organic chemistry, and pharmaceutical and pharmaceutical chemistry, as well as analytical procedures and techniques for analytical chemistry, synthetic organic chemistry, and pharmaceutical and pharmaceutical chemistry are known in the art. Standard techniques are used in chemical synthesis, chemical analysis, pharmaceutical preparation, formulation and delivery, and in the treatment of patients. Reaction and purification techniques can be performed, for example, using a kit with manufacturer's instructions, or as commonly done in such techniques or as described herein. The above techniques and procedures are generally performed in accordance with the conventional methods well known in the art and as described in the various general and more specific references cited and discussed throughout the specification. Throughout the specification, groups and substituents thereof may be selected by those skilled in the art to provide stable moieties and compounds. The compounds provided herein can exist as tautomers. A tautomer is a compound which can be converted by a hydrogen atom and which is converted by a single bond and an adjacent double bond. In solutions that may be tautomerized, there will be a chemical equilibrium of the tautomers. The exact ratio of tautomers depends on several factors including temperature, solvent and pH. Some examples of tautomeric pairs include: 144535.doc -28- 201023852

OH V^NH

OH vV,

H V^NH;

"Pharmaceutically acceptable derivative or prodrug" as used herein means any pharmaceutically acceptable salt, ester, ester salt or other derivative of a compound which, after administration to a recipient It is capable of providing (directly or indirectly) a pharmaceutically active metabolite or a residue thereof. Particularly advantageous derivatives and prodrugs are those which, when administered to a patient, increase the bioavailability of such compounds (eg, by allowing the orally administered compound to be more readily absorbed into the blood) or to promote the parent compound to the biological metabolic zone. A derivative or prodrug that is transmitted by (bi〇1〇gieal, such as the brain or lymphatic system). Compartment (for example, the term "pharmaceutically acceptable U" refers to a salt which retains the biological effectiveness of the free acid and base of the specified compound and which is not biologically or otherwise unsuitable. The compounds described herein may have an acidity or test. And can thus react with any of a variety of inorganic or organic bases and inorganic and organic acids to form pharmaceutically acceptable salts. These salts can be prepared on-site during the final isolation and purification of the compound, or by liberating The purified compound of the test form is separately reacted with a suitable organic or inorganic acid, and the salt thus formed is isolated. Examples of the pharmaceutically acceptable salt include salts prepared by reacting a compound with an inorganic or organic acid or an inorganic base, Such salts include acetates, acrylates, adipates, alginates, aspartates, benzoates, besylate, hydrogen sulfate, bisulfites, bromides, butyrates. , butyne-1,4-diformate, camphorate, camphorsulfonate, hexanoic acid 144535.doc -29- 201023852 salt, caprylate, benzoate, chloride, citrate, ring E Propionate, citrate, digluconate, dihydrogen phosphate, dinitrophenyl phthalate, dodecyl sulfate, ethanesulfonate, citrate, thiocyanate, Glucosamine, glycerol phosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-ι, 6-diformate, hydroxybenzoate, γ-hydroxybutyrate , hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate , mandelate, metaphosphate, methanesulfonate, mercaptobenzoate, methyl benzoate, hydrogen phosphate, 1-naphthalene sulfonate, 2-indolyl naphthalene sulfonate, nicotine Acid salts, nitrates, palmate, pectate, peroxysulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, coke Sulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfurous acid Salt, succinate, suberate Sebacate, sulfonate, tartrate, thiocyanate, tosylate, undecanoate and dinonylbenzene sulfonate. Other acids such as oxalic acid, although not themselves pharmaceutically acceptable , but it can be used to prepare a salt suitable as an intermediate in obtaining the compounds described herein and their pharmaceutically acceptable acid addition salts. See, for example, Berge et al., J. phann.

Sci· 1977, 66, 1-19. Additionally, the compounds described herein which may comprise a free acid group may be reacted with a suitable base such as a hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation, ammonia or pharmaceutically acceptable Organic primary, secondary or tertiary amines. Representative alkali or alkaline earth salts include lithium, sodium, potassium, calcium, magnesium and aluminum salts and the like. Illustrative of the base 144535.doc •30· 201023852 Examples include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N+iC!.4 alkyl h and the like. Representative organic amines suitable for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, iethanolamine, piperazine and the like. It is understood that the compound also includes quaternization of any basic nitrogen-containing groups that it may contain. Water or oil soluble or dispersible products are obtained by this quaternization. See, for example, the aforementioned Berge et al. Children/it phenolic phenolic hospitals can also exist in various polycrystalline states in various polycrystalline states.

/ affixed herein' and may also be suitable for treating conditions. For example, in an embodiment of the methods described herein, a polymorphic form of catechin can be administered. Catechol butane includes, for example, all crystalline forms (referred to as polymorphs). Polymorph 1 includes different crystal packing arrangements of the same element composition. Polymorphs can have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, (tetra) and solubility. A variety of factors, such as recrystallization solvent, crystallization rate, and storage temperature, can cause premature crystal forms to dominate. Various polymorphs can be administered in the form of a pharmaceutical composition. In a pharmaceutical dosage form, the active agent may be administered in the form of a pharmaceutically acceptable salt thereof, or it may be used alone or in combination with other pharmaceutically active compounds. The following methods and excipients are merely illustrative and do not make the invention in any square wire. Methods of preparing various pharmaceutical compositions with a particular amount of active compound are known or readily apparent to those skilled in the art. See, for example, Remington's Pharmaceuticai Sciences, Mack Publlshing CGmpany, Ester, pa, 18th ed. (19. Pharmaceutically acceptable excipients (such as vehicles, adjuvants, swords or 144535.doc • 31 - 201023852) Agents are well known in the art. Suitable excipients are, for example, water, physiological saline, dextrose, glycerol, ethanol or the like and combinations thereof. In addition, the right agent may contain a small amount of auxiliary substances. Such as pH adjusting agents and buffers, tonicity adjusting agents, stabilizers, wetting agents or emulsifiers. The actual method of preparing such dosage forms is known or apparent to those skilled in the art. See, for example, Remington's Pharmaceutical Sciences, Mack Publishing. C〇mpany, Easton, Pa., 17th edition, 1985. In any event, the composition or formulation to be administered should contain an amount of the agent sufficient to achieve the desired state in the individual to be treated. Dissolve, suspend or emulsify it in an aqueous or non-aqueous solvent (such as vegetable oil or other similar oils, including corn oil, castor oil, synthetic aliphatic acid glycerol , in the presence of a high-carbon aliphatic acid or a propylene glycol ester; and if necessary, in the presence of conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifiers, stabilizers, and preservatives, for injectable use. The aqueous suspension contains the active substance in admixture with excipients which are suitable for the preparation of aqueous suspensions. These excipients are: suspending agents such as sodium carboxymethylcellulose, methylcellulose, propylmethyl Cellulose, sodium alginate, polyvinylpyrrolidone, tragacanth and acacia; the dispersing or wetting agent can be a naturally occurring phospholipid, such as lecithin, or a condensation product of an alkylene oxide with a fatty acid (eg Polyoxyethylene stearate §|), or a condensation product of ethylene bromide with a long-chain aliphatic alcohol (such as hepta-ethyloxyhexadecanol), or epoxy acetophenone and derivative = self-fatty acid a condensation product of a partial ester of hexitol, such as polyoxyethylene sorbitan monooleate, or a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (eg, polyethylene sorbitan) Alcohol monooleic acid I44535.doc 201023852 vinegar). Waterborne The float may also contain - or a plurality of preservatives (for example, ethylparaben or propylparaben), or a plurality of coloring agents, one or more flavoring agents, and one or more sweeteners (such as P twist, such as reading, saccharin or aspen C* sweet j. Pharmaceutical preparations may be formulated for parenteral administration by injection (for example by bolus injection or continuous infusion). Formulations for injection may be in unit dosage form ( For example, in ampoules or multi-dose containers, with the added preservatives, the composition may be in the form of a suspension, solution or emulsion, such as in an oily or aqueous vehicle, and may contain a formulation, such as a suspension. Agents, stabilizers and/or dispersants. Formulations may be provided in unit dose or multi-dose containers (eg, sealed ampoules and vials) and may be stored in powder form or stored in cold-dried Donggan) and only require sterile (four) carriers prior to use. (eg physiological saline or sterile pyrogen-free water). Injectable solutions and suspensions can be prepared from the above-mentioned sterile powders, granules and lozenges. Formulations for parenteral administration include aqueous and non-aqueous (oily) sterile injectable solutions of active compounds which may contain antioxidants, buffers, biocides, bacteriostatic agents, and the formulation and intended recipients An isotonic solute of blood; and an aqueous and non-aqueous g-free suspension, which may include a suspending agent and a thickening agent. Examples of suitable isotonic vehicles for such formulations include gasified nanoinjections, Ringer's solution (Laring, s soluti) or Lactated Ringer (s Injec U〇n). Suitable lipophilic solvents or vehicles include fatty oils (such as sesame oil) or synthetic fatty acid esters (such as ethyl oleate or acid glycerol) or sorghum plastids, or other particulate systems that can be used to dry the compound to the blood peak or - ❹ an organ. The concentration of the active ingredient of the money towel can be 144535.doc -33· 201023852 Wide change. Typically, the concentration of the active ingredient in the solution is from about 1 ng/ml to about μ§, for example from about 10 ng/ml to about 1 Pg/m. Aqueous injection suspensions containing substances which increase the viscosity of the suspension, such as methyl cellulose. Na, mountain, sugar alcohol or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which improve the solubility of the compound so that a high concentration of solution can be prepared. The pharmaceutical preparation can also be formulated as a storage tank type preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. The chemical substance may be formulated, for example, with a suitable polymeric or hydrophobic substance (for example, an emulsion formulated in an oil) or an ion exchange resin, or may be formulated as a poorly soluble derivative (for example, formulated as a poorly soluble salt). For buccal or sublingual administration, the composition may be in the form of a tablet, tablet or gel in a conventional manner. The compositions may be included in a flavoring base such as a curtain of sugar and gum arabic or jaundice Active ingredient 0 The pharmaceutical preparation can be administered topically, that is, by non-systemic administration. This includes external application of the composition to the epidermis or buccal cavity, and dropping the compound into the ear, eyes and nose so that the compound does not It will enter the bloodstream significantly. In contrast, full-body administration refers to oral, intravenous, intraperitoneal, and intramuscular administration. Pharmaceutical preparations suitable for topical administration include liquids that are applied to the inflamed area through the skin. Or a semi-liquid preparation, such as a gel, a foaming agent, a lotion, a cream, an ointment or a paste, suitable for administration to the eye, ear or nose 35 floats, powders, solutions, sprays, gases (four), oil agent Drops. The formulation may comprise a patch or dressing such as a bandage or an indomethacin soaked with the active ingredient and optionally one or more excipients or diluents. Local H4535.doc •34- 201023852 The amount of active ingredient present may vary widely. For topical administration, the active ingredient may constitute from 0.001% to 1% w/w, for example from 1% to 2% by weight of the formulation. However, it may constitute up to 10 % w/w, but preferably should constitute a formulation of 5 °/.w/w or less 'better than 1% to 1%. Formulations suitable for topical administration include mouth-containing ingots, which are included in the flavoring matrix. (usually sucrose and gum arabic or tragacanth) 10 active ingredients; tablets, contained in an inert matrix (such as gelatin and glycerin, or sucrose and ar

An active ingredient in a labric gum; and a mouthwash comprising the active ingredient in a suitable liquid carrier. Formulations suitable for topical administration to the eye also include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier (especially an aqueous solvent of the active ingredient). The active agent can be used in the form of an aerosol formulation for administration by inhalation. The compounds of the presently disclosed embodiments can be formulated into acceptable pressurized propellants such as difluorodifluorodecane, propane, nitrogen, and the like. Further, the active agent can be prepared as a suppository by mixing with a variety of substrates such as an emulsifying base or a water-soluble base. The compounds of the embodiments of the invention may be administered rectally via a suppository. The suppository may include a vehicle such as cocoa butter, carbonium and polyethylene glycol which melts at body temperature but solidifies at room temperature. For oral preparations, the active agents may be used alone or in combination with suitable additives to prepare lozenges, powders, granules or capsules: conventional additives such as lactose, mannitol, corn starch, potato powder, adhesives, such as Crystalline cellulose, cellulose derivative, gum arabic, corn house powder or alum; collapse (four) 'such as jade (four) powder, potato (four) slit methyl cellulose sodium; lubricant 'such as talc or magnesium stearate; If necessary, it can be diluted with 144535.doc •35- 201023852, slow _, wet _, anti-money and seasoning (four). Oral lotions can be prepared in a manner customary in the art. Unit dosage forms (such as sugar, brew, and suspension) for trans- or rectal administration may be provided, wherein each dosage unit (eg, _ teaspoon, one tablespoon, lozenge or suppository) contains a predetermined amount of Or a combination of a plurality of inhibitors. Similarly, unit dosage forms for injection or intravenous administration may contain the inhibitor in compositions in the form of a mixture of sterile water, standard physiological saline or another pharmaceutically acceptable carrier. Some catechol butanes are water-soluble hydrophilic compounds. Some embodiments include formulating a hydrophilic compound in a pharmaceutically acceptable carrier or excipient and delivering such as oral formulation 16, such as in the form of an aqueous liquid solution of the compound t or the compound can be dried by bead and delivered in powder form, Tablets or compounds can be formulated to be encapsulated. The tablet of the present invention may be an agent coated with an enteric coating. Formulations herein can be sustained release formulations, i.e., slow release or rapid release of the formulation. The amount of catechol butane included in the oral formulation can be adjusted to the dosage to be administered to the individual. This adjustment is within the scope of the personal technology known in the art. Some of them are hydrophobic or lipophilic compounds. Absorption of the lipophilic compound in the digestive tract can be improved by the use of a pharmaceutically acceptable carrier which promotes the rate or extent of dissolution of the compound in the aqueous intestinal fluid. Lipids are known in the art. Formulations herein can be delivered orally in liquid form or can be encapsulated into a variety of capsules. An embodiment of the invention includes, in one example, a lipophilic catechol butane containing 144535.doc • 36-201023852 a formulation which is formulated for oral delivery by dissolving the compounds in triglycerides 'and then the formulation is encapsulated for oral delivery. Triglyceride is a molecule in which long-chain and/or medium-chain fatty acids are linked to glycerol molecules. Long chain fatty acids range from about Cm to CM and can be found in common fats. The medium chain fatty acid is between about (2 to 2) and may be present in coconut oil or palm linseed oil. Triglycerides suitable for use herein include structured lipids which contain short bonds esterified on the same glycerol molecule. Or a medium chain fatty acid or a mixture of the two. In another embodiment, one or more surfactants may be added to the mixture of catechol butane and the lipid carrier to make the drug an oil/surfactant mixture The droplet form is present. The surfactant can act to disperse the oily formulation when diluted in the gastrointestinal fluid. Embodiments of the invention also include formulations for the oral delivery of catechol butane in the form of a microemulsion, which Hydrophilic surfactant and oil composition. The microemulsion particles may be surfactant microcapsules containing dissolved oil and drugs. Formulations suitable for oral administration may be provided in the form of discontinuous units such as each containing a predetermined amount Capsules, blisters or lozenges of active ingredients; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; or oil-in-water liquid emulsions or water-in-oil liquid emulsions. Sexual ingredients may also be provided in the form of a bolus, tincture or paste. Pharmaceutical preparations which can be used orally include lozenges, co-inserted capsules made of gelatin, and plasticizers such as gelatin and glycerin or sorbitol. A soft-sealed capsule made of a tablet. The tablet can be prepared by compression or molding, optionally with one or more accessory ingredients. The compressed tablet can be compressed in a free-flowing form by 144535.doc -37-201023852 in a suitable machine. Preparation of active ingredients (such as in the form of powders or granules), optionally mixed with the following: binders (eg, polyvinylpyrrolidone, gelatin, hydroxypropyl methylcellulose), inert diluents, preservatives, disintegration Decomposing agents (such as sodium starch glycolate, crosslinked polyvinylpyrrolidone, croscarmellose sodium) or lubricants, surfactants or dispersing agents. Molded tablets can be molded in a suitable machine. Prepared by mixing a mixture of powdered compounds moistened with an inert liquid diluent. The spinner may optionally be coated or scored and formulated to provide slow or controlled active ingredients therein. The tablet may optionally be coated with an enteric coating to release it in addition to the stomach in the digestive tract. All formulations for oral administration should be in dosages suitable for such administration. a mixture of ingredients and fillers (such as lactose), binders (such as starch) and/or lubricants (such as talc or magnesium stearate) and optionally stabilizers. In soft capsules, the active compound can be dissolved or suspended. In a suitable liquid such as a fatty oil, liquid paraffin or liquid polyethylene glycol. In addition, a stabilizer may be added. The dragee core has a suitable coating. For this purpose, a concentrated sugar solution may be used, which may optionally contain gum arabic, Talc, polyvinylpyrrolidone, polyacrylic acid gel, polyethylene glycol and/or cerium oxide, lacquer and suitable organic solvent or solvent mixture. Dyestuffs or pigments can be added to tablets or dragee coatings for Clockwise or characterize different combinations of active compound doses. The catechol butane formulation in the form of a solid lipid nanoparticle formulation is also suitable for oral administration. Solid lipid nanoparticles can be prepared in any manner known in the art. In the embodiment, the solid lipid nanoparticle can be prepared by homogenizing the lipid at a high temperature in a heat homogenization process. During this process, the solid lipid is melted and catechol butane is dissolved in the molten lipid. The preheated dispersion medium is then mixed with the drug-loaded lipid melt, and the combination is mixed with a homogenizer to form a crude pre-emulsion. High pressure homogenization is then carried out at a temperature above the melting point of the lipid to produce an oil/water_nano emulsion. The nanoemulsion was cooled to room temperature to form solid lipid nanoparticles. In another embodiment, the solid lipid nanoparticles can be prepared in a cold homogenization process towel. In the process, 'the lipid is melted' and the catechin is dissolved in the molten lipid. The drug-loaded lipid is then allowed to solidify in liquid nitrogen or dry ice. The solid drug_lipid was ground in a powder mill to form 5〇_1〇〇 μιη particles. The lipid particles are then dispersed in a cold aqueous dispersion medium and homogenized at room temperature or below to form solid lipid nanoparticles. In one example, a lipophilic or microcell form of a lipophilic f-tea syrup formulation is also provided herein for oral delivery. These formulations can be prepared in any manner known in the art. The microcells are typically lipid monolayers/packages in which a hydrophobic drug associates with a hydrophobic region on a monolayer. Liposomes are typically fat-filled bilayer vesicles. Lipophilic catechus are expected to be present in the center of such vesicles. - In another example, formulations for intravenous administration of catechol butyrate are also provided herein. The catechin-old calcined can be formulated for use with/from the pharmaceutically acceptable carrier. The carrier includes, but is not limited to, one or more solubilizing agents and/or excipients, such as: (4) water soluble in addition to dimethyl sulfoxide &amp; H with the limitation that when the water soluble organic solvent is propylene glycol, the propylene glycol is in There is no white stone ant fat, Sanxian 朦 (xanthan gum, 144535.doc · 39· 201023852 xantham gum) and at least at least glycerol or glycine, when the water-soluble organic solvent is polyethylene glycol, polyethylene The diol is present in the absence of ascorbic acid: 5 in the presence of terpene toluene ("BHT") and when polyethylene glycol is polyethylene glycol diol polyethylene glycol 400 in the absence of polyethylene glycol 8000 (b) cyclodextrin; (e) ionic, nonionic or amphoteric interfacial activator. The limiting condition is that when the surfactant is a nonionic surfactant, the nonionic surfactant is not (4) modified cellulose, (e) water-insoluble lipid other than onion oil; or a combination of any one of carriers (10) (e). / Drug, and the substance may be in the form of a sterile injectable aqueous solution. The acceptable vehicles and solvents that can be used are water, Ringer's solution and isotonic sodium solution. The sterile injectable preparation may also be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase I. For example, the active ingredient is first dissolved in a mixture of soybean oil and lecithin. The oil solution is then introduced into the water and glycerin mixture and processed to form a microemulsion. The injectable solution or microemulsion can be introduced into the patient's bloodstream by local rapid injection. Alternatively, it is preferred to administer the solution or microemulsion &amp; while maintaining the concentration of the compound of the present invention. To maintain this constant concentration, a continuous intravenous delivery device can be used. An example of such a device is the Dehec CADD_PLUSTM Model 54 〇〇 intravenous pump. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oily suspension for intramuscular and subcutaneous administration. This suspension may be formulated according to known techniques using the appropriate dispersing agents or wet turbid and suspending agents described above. The sterile injectable preparation may also be in the form of a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, a solution in the form of butanediol. In addition, 'sterile ^ 144535.doc -40- 201023852 Hair oil is usually used as a solvent or suspension medium.. ^ _ For the purpose of this, you can use any non-stinging pure non-volatile oil, including synthetic monoglyceride or two Acid glycerin. In addition, fatty acids such as oleic acid find use in the preparation of injectables. Formulations for intra-arterial administration (IV) butadiene are also provided herein with or without associated blood-brain barrier disruption ("B-excitation") and with or without obstruction (such as in hepatic arterial chemoembolization). In short, if the arteries are administered in the arteries under occlusion, the initial arterial insertion to the target site

The catheter and the (four) butadiene can be administered via a catheter. In order to keep the catechins in the target position for a long period of time, the arteries can be embolized by using the polyethylene particles alone or in combination with the coil. Intra-arterial delivery of catechin can include a water soluble composition. The drug or agent herein can be dissolved in physiological saline followed by intravenous infusion &amp; and heparin therapy and sedation can be performed prior to the injection. The osmotic destruction of the blood-brain barrier ("BBB") known in the art can be accompanied by intra-arterial delivery of the agent herein. It may be preferred to use the delta metaprogram just prior to intra-arterial delivery to facilitate drug transfer to the central nervous system ("CNS"). To perform this disruption, the catheter is placed in the artery leading to the brain, usually the superficial temporal artery, and the sputum is destroyed with a mannitol solution. This invasive procedure is usually performed under general anesthesia. This therapy may require pre-hydration and administration of anticonvulsants and/or atropine. In one example, a formulation of catechol-butylate for intranasal delivery and intranasal delivery thereof is also provided herein. Intranasal delivery can advantageously form a higher concentration of active agent in the brain compared to the concentration achieved by intravenous administration. This delivery also avoids the first generation of the liver and digestive tract in individuals receiving the drug. 144535.doc • 41 _ 201023852 Thanks for the question. The amount of active agent that can be absorbed depends in part on the solubility of the drug in the mucus, which is a composition consisting of a serum protein, a glycoprotein, a lipid, and an electrolyte. In general, as the activity of the active agent herein increases, the concentration of the drug in the CSF also increases. Hydrophilic catechu is expected to be soluble in pharmaceutically acceptable carriers (such as physiological salt I, citrate buffer, liquid or discate buffered physiological saline) φ

in. In one embodiment, G. 〇5 trans-acid salt buffer (pH can be used as a carrier. The intranasal delivery of the agent of the present invention can be optimal by adjusting the position of the individual at the time of administration. For example, The patient's head can be erected to the ruling team _ 9 〇., supine _45. or supine _7 〇. Different placement for maximum effect. φ catechin composition can be medicinal ± acceptable and Any substance q carrier which is compatible with the active agent of (4) &amp; is a liquid, which may be low osmotic pressure or isotonic with nasal fluid, and has a p Η value of about 45 to about 2. If the carrier is in the form of a powder The composition of the carrier for intranasal delivery may optionally contain a lipophilic substance that promotes absorption of the active agent through the nasal membrane and into the brain via the olfactory nerve pathway. Examples include, but are not limited to, nerve knots (four) and several lipid-lipid adjuvants of the squamous lipids, which can be administered intranasally to an individual to treat the medicament. MM I The disease, disorder or disease of the present invention The activity of this type is as described in the conventional method described in, for example, U.S. Patent No. 6,18, MG3, This patent is incorporated herein by reference in its entirety by reference. For example, the compositions herein can be formulated as powders, granules, solutions, aerosols, drops, nanoparticles or liposomes. The composition may contain, in addition to the active agent, a suitable adjuvant, buffer, preservative, salt. Solutions such as nasal drops may contain antioxidants, buffers, and the like. The catechol butane can be delivered to the individual for treatment by surgical implantation into the desired site, such as by implantation of a biodegradable polymer containing catechol butane. Thus, the biodegradable polymer herein can be any polymer or copolymer that will dissolve in the interstitial fluid without any toxicity or side effects to the host tissue. The monomer of the polymer or synthetic polymer is preferably approved for human administration by the Food and Drug Administration. The copolymer of monomers having different solubility characteristics preferably allows control of the degradation kinetics, such as increasing the ratio of one monomer to another to control the rate of dissolution. In one embodiment, as described by Fleming AB and Saltzman, WM, Pharmacokinetics of the Carmustine Implant, Clin. Pharmacokinet, 41: 403-419 (2002); and Brem, H. and Gabikian, P. (2001), polymerization The product is a copolymer of 1,3_bis-(p-carboxyphenoxy)propane and sebacic acid [p(CPP:SA)]. In another embodiment, the polymer is a copolymer of polyethylene glycol ("PEG") and sebacic acid as described by Fu, J. et al., (2002) Biomaterials, 23: 4425-4433. The polymer delivery system can be used to deliver the hydrophobic and hydrophilic catechol butadiene described herein. The catechol butane can be combined with the biodegradable polymer and surgically implanted at the desired or affected site. Some polymerizations 144535.doc • 43· 201023852 Compositions can also be used for intravenous or inhalation therapy herein. The catechol butane can be delivered systemically and/or by local administration by inhalation. Inhaled delivery of drugs has been widely used as a method of obtaining higher drug concentrations in lung tissue without triggering substantial systemic toxicity and a means of achieving systemic circulation of the drug. Techniques for producing such formulations are known in the art. Hydrophobic or hydrophilic catechol butane delivered in this manner can be seen to be effective against lung diseases. For delivery via the inhaled lung, 'catechol butane can be formulated into a dry powder, an aqueous solution, a liposome, a nanoparticle or a polymer and is administered, for example, in the form of an aerosol. The hydrophilic barrier can also be absorbed through the alveolar surface and into the bloodstream for systemic administration. In one embodiment, a polymer of the active agent herein is prepared and used as described in Fu, j. et al., (2, 2). For example, the polymer herein may be a polymer of six and polyethylenol ("pEG"), or may be poly(lactic-co-lactic acid) ("PLGA") or polyethylene ("pEi"). A polymer of poly(amino acid) ("PLL"). In another embodiment, the tea for inhalation delivery may be dissolved in © physiological saline or ethanol followed by nebulization and administration. In the examples, the agents herein are also effective when delivered as a dry powder prepared in a manner known in the art. In an embodiment, delivery of the NDGA compound can be accomplished by embedding into a drug delivery device, a microprocessor (such as SmartMistTM &amp; AERxtm). The appropriate dose to be administered depends on the individual to be treated, such as an individual. 144535.doc 44· 201023852 The age of a healthy individual, the condition of the disease or condition, the weight of the individual, and the size of the tumor. ♦ Pharmaceutical compositions may be formulated for use in the following routes of administration, such as intranasal administration: oral administration; inhalation administration; subcutaneous administration; transdermal administration; intra-arterial injection, with or without obstruction; intracranial Dosing; indoor administration; static: internal administration, buccal administration; intraperitoneal administration; intraocular administration; intramuscular administration; implant administration; and central intravenous administration. In one embodiment, the catechu is formulated for oral administration. In another embodiment, the catechin is formulated for intravenous administration. The preferred dosage of the active agent for administration of a single dose in a single or more usual dose can be readily determined by a variety of methods by those skilled in the art. Other effective dosages can be readily determined by routine experimentation by those skilled in the art via the establishment of a dose response curve. The amount of the agent will of course vary depending on the particular agent being used. The frequency of administration of the active agent at such doses should be determined by the caregiver based on age, weight, disease condition, health status, and patient response. Thus, the administration of the drug can be determined as usual, one or more times per day, week, month, or as needed. The agent may be administered intermittently, such as for several days, weeks, or months, and then until a certain period of time, such as 3 months or 6 months, and then cast for several days, weeks, or weeks. month. The unit dosage form for injection or intravenous administration may comprise an API in a composition of the solution in sterile water, standard physiological saline or another pharmaceutically acceptable carrier. Mechanism of catechol butane 144535.doc -45- 201023852 Without wishing to be bound by a mechanism of action, the inventors have discovered that the compounds described herein via the dual inhibitory receptor tyrosine kinase (RTK) EGFR IGF-1R has anti-proliferative properties. The mechanism of action of this drug is related to its ability to act as a dual kinase inhibitor of EGFR and IGF-1R. There are multiple interactions between insulin-like growth factor-1 receptor (IGF-1R) and epidermal growth factor receptor (EGFR), which together have a significant impact on tumor biology and cancer treatment. This interaction comes from the degree of redundancy of its function, in which the two receptors conduct signals via a common proliferative and survival pathway. In addition, there is crosstalk between the two receptor signaling pathways such that signaling through one receptor can activate another receptor via a ligand-dependent or independent mechanism. This redundancy and crosstalk raises the main problem of anti-cancer treatment targeting the target. The efficacy of targeting interventions that block EGFR function in cells may be limited, and for these cells, activated IGF-1R signaling may activate many downstream effector molecules involved in mediating EGFR action. A decrease in sensitivity to IGF-IR inhibition may also be attributed to an increase in EGFR expression or activity. More importantly, drug resistance to EGFR and HER2 treatment is associated with upregulation of the IGF-1R signaling pathway. This enhancement of IGF-IR signaling can prevent EGFR inhibition by providing alternative proliferation and survival signals, as well as by independently increasing EGFR ligand production or independently stimulating EGFR activation via direct phosphorylation. The role of IGF-1R in resistance to EGFR targeting agents suggests that promising new therapies and improved strategies for treating tumors are driven by EGFR activity. In support of this proposal, cell lines resistant to gefitinib (Iressa®) producing 144535.doc -46-201023852 showed up-regulation of IGF-1R signaling and increased sensitivity to therapy targeting IGF-1R. Although NDGA is known to be primarily an inhibitor of 5' and 12' lipoxygenases, the inventors have shown that direct inhibition of purified IGF with greater affinity compared to the effect of this molecule on purified lipoxygenase -1R and EGFR tyrosine kinase activity. See Figure 1. Thus, NDGA is a promising agent for the treatment of tumors that overexpress EGFR and IGF-1R to prevent targeting only EGFR or only IGF-1R. NDGA is also a promising agent for patients who are resistant to gefitini® therapy. Inhibition of the activity of EGFR and/or IGF-1R involves reducing the activity of such molecules. The term "inhibition" and its grammatical variations (such as "inhibiting") are not intended to require a complete reduction in EGFR and/or IGF-1R activity. The reduction can be at least about 10%, at least about 15%, at least about 20% of the molecular activity without inhibition (e.g., in the absence of an inhibitor such as the catechol butane described herein). At least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 75%, at least about 80%, at least about 85%, at least about 90% Or at least about 95%. The term also refers to a decrease in activity that is observable or measurable. In the case of treatment, inhibition is preferably sufficient to produce a therapeutic and/or prophylactic benefit in the condition being treated. The phrase "non-inhibition" and its grammatical variations do not require a complete lack of activity. By way of example, it refers to a situation in which the reduction in EGFR and/or IGF-1R activity is less than about 50%, less than about 40%, in the presence of an inhibitor such as the catechol butane described herein. Below about 30%, below about 20%, below about 10°/. Or less than about 5%. 144535.doc -47- 201023852 Use of catechol butane The catechol butane can sensitize cancer or other proliferative diseases to known therapies, and to make cancer or other proliferative diseases acquired in these conventional therapies Sensitive after resistance. The embodiments described herein provide a method of inhibiting EGFR and IGF-1R in a cell comprising contacting a cell in need of inhibition of EGFR and IGF-1R with a catechol butane described herein. Because the compounds described herein are dual kinase inhibitors, they are a suitable research tool for studying the role of EGFR and IGF-1R in biological processes in vitro. Xu Ding provides a method for screening individuals for levels of IGF-1R and EGFR tyrosine kinase activity, comprising: (i) analyzing a sample obtained from an individual comprising measuring the levels of IGF-1R and EGFR; and (ii) The content of IGF-1R and EGFR in the sample was compared with that in the control group. Provided herein are methods for determining disease therapy comprising: (i) analyzing a sample obtained from an individual comprising measuring the levels of IGF-1R and EGFR, and (ii) measuring the amount of IGF-1R and EGFR in the sample with a control The contents were compared; an increase in the levels of IGF-1R, EGFR, or both compared to the control indicated that the individual was treated with a dual tyrosine kinase inhibitor. In one embodiment, the dual tyrosine kinase inhibitor is a catechol butane such as described herein. In one embodiment, the EGFR expression is at or above baseline and the IGF-IR performance is baseline or exceeds baseline. In another embodiment, the EGFR expression is baseline and the IGF-IR performance is 2 or more times the baseline content. In another embodiment, the IGF-1R performance is 144535.doc -48-201023852 is the baseline level and the EGFR performance is 2 or more times the baseline level. In another embodiment, the IGF-1R expression is 2 or more times the baseline level and the EGFR expression is 2 or more times the baseline level. In one aspect, IGF-1R and EGFR can be analyzed by the following steps: (4) introducing a labeled antibody against IGF-1R to an individual and a labeled s-antibody against EGFR' and (b) by standard imaging techniques. These labeled antibodies are speculated. The antibody can be labeled with a radioactive label whose presence and location in the individual can be detected by standard imaging techniques. In one embodiment, the antibody to IGF-1R and the antibody to EGFR are different in radiolabeling. In one aspect, the method may further comprise administering to the individual a pharmaceutical compound capable of inhibiting tyrosine kinase activity of IGF-1R and EGF-R, wherein the pharmaceutical compound is a catechin inhibiting IGF-1R and EGFR burn. To assess the performance of a tumor cell biomarker, a patient sample containing a tumor cell or a protein or nucleic acid produced by such a tumor cell is used in the method described in, for example, US Publication No. 20070065858, which is incorporated by reference in its entirety. The way is incorporated in this article. Briefly, the amount of biomarker expression can be assessed by measuring tumor cell samples (eg, tumor biopsies obtained from patients or other patient samples containing tumor-derived substances (eg, blood, serum, urine, or other body fluids described herein above or The amount of label (eg, absolute amount or concentration) in the secretion)) is assessed. The cell sample can of course be subjected to a variety of well-known post-collection preparation and storage techniques (eg, nucleic acid and/or protein extraction, immobilization, storage, freezing, super-pass, concentration, evaporation, centrifugation, etc.) prior to assessing the amount of label in the sample. 'Tumor biopsy can also be subjected to post-collection preparation and storage techniques (eg, fixation). 144535.doc -49· 201023852 We can detect the expression of biomarker proteins, at least a part of which are presented on the surface of the tumor cells expressing them. We can determine whether the marker protein or a part of it is exposed on the cell surface. For example, immunological methods can be used to detect such proteins on whole cells or at least one extracellular domain (ie, including secreted proteins and proteins having at least one cell surface domain) can be predicted using well-known computer-based sequence analysis methods. Existence. The expression of the marker protein can be detected without lysis of the tumor cells (e.g., using a labeled antibody that specifically binds to the cell surface domain of the protein), at least a portion of which is present on the surface of the cell in which it is expressed. The performance of a biomarker can be assessed by any of a variety of well known methods for detecting the expression of a transcribed nucleic acid or protein. Non-limiting examples of such methods include, for example, immunological methods for detecting cytoplasm or nuclear protein on the surface of secreted cells, protein purification methods, protein function or activity assays, nucleic acid hybridization methods, nucleic acid reverse transcription methods, and nucleic acid amplification methods or Any other method known in the art. The expression of the beta biomarker can be assessed using antibodies (eg, radiolabeled, fluorophore-labeled or enzymatically labeled antibodies), antibody derivatives (eg, with a substrate or a protein-ligand pair (eg, biotin) - an antibody against the protein or ligand bound by antibiotic egg = cytocin) or an antibody fragment (10) a single bond antibody, a hypervariable domain of an isolated antibody, etc., which specifically binds to a raw &quot;&quot;, a protein or Fragments, including biomarker proteins that have undergone all or a portion of post-translational modifications (eg, glycosylation, phosphorylation, methylation, etc.) wherein the protein is typically subjected to such modifications in tumor cells. 144535.doc 201023852

The biomarker can also be characterized by the preparation of mRNA/cDNA (i.e., the transcribed polynucleotide) from cells in the patient sample and by reference nucleation of the mRNA/cDNA to the complement of the biomarker nucleic acid or fragment thereof. Glycoside hybridization was used to assess. The cDNA may be amplified using any of a variety of polymerase chain reaction methods, optionally followed by hybridization with a reference polynucleotide. One or more biomarkers can also be used to quantify the performance of one or more biomarkers using quantitative PCR detection. Alternatively, the presence of a biomarker in a patient can be detected using any of a number of known methods for detecting a mutation or mutation (e.g., single nucleotide polymorphism, deletion, etc.) of a biomarker. The mixture of transcribed polynucleotides obtained from the sample can be contacted with a substrate that is immobilized with at least a portion of the biomarker nucleic acid (eg, 7, 10, 15, 2, 25, 3, 4, 4) A polynucleotide that is complementary or homologous to 〇, 5〇, 1〇〇, $(8), or 5 (9) or more nucleotide residues). A single receptor can be used if the complementary or homologous polynucleotides are differentially detected in the receptor (for example, using different chromophores or fluorophores or immobilized at different selected positions) For example, a "gene wafer" microarray of polynucleic acid immobilized at a selected location simultaneously sifts the amount of performance of a plurality of biomarkers. If a method for assessing the expression of a biomarker involving hybridization of one nucleic acid to another nucleic acid is used, hybridization can be performed under stringent hybridization conditions. If a plurality of biomarkers are used in the methods described herein, the sigma can be reacted in a single reaction (ie, using an elixir such as a different fluorescent probe for each biomarker) or in an individual reaction mixture corresponding to - or multiple biomarkers. Will be like. The amount of expression of each biomarker in σ is compared to the normal amount of each of the plurality of biomarkers in the same type of non-cancerous sample. 144535.doc -51 - 201023852 There are several ways to assess the amount of biomarkers in normal (ie, non-cancerous) human tissues. This normal amount of expression can be assessed by assessing the amount of expression of the biomarker in a portion of the cells that are presented as non-cancerous, and then comparing the normal amount of expression to the amount of expression in a portion of the tumor cells. As other information becomes available as a result of routine implementation of the methods described herein, the normal average of the biomarkers can be used. Alternatively, the normal amount of biomarker can be determined by assessing the biomarker profile in a patient sample: a patient sample obtained from a non-cancerous cancer patient, a patient sample obtained from the patient prior to the suspected cancer onset, and a Patient samples and their similar patient samples. Exemplary methods for detecting the presence of a biomarker protein or nucleic acid in a biological sample include obtaining a biological sample (eg, a tumor-associated body fluid) from the test subject and enabling the biological sample to detect a polypeptide or nucleic acid (eg, mRNA, genomic DNA, or cDNA). The compound or agent is in contact. Therefore, such detection methods can be used to detect biological samples such as mRNA, protein, cDNA or genomic DNA in vitro and in vivo. In vitro techniques for detecting mRNA include, for example, Northern hybridization and in situ hybridization. In vitro techniques for detecting biomarker proteins include, but are not limited to, enzyme-linked immunosorbent assay (eusa), Western blotting, immunohistochemistry, immunoprecipitation, and immunofluorescence. In vitro techniques for detecting genomic DNA include, for example, Southern hybridization. In vivo techniques for detecting melons include, for example, polymerase chain reaction (PCR), northern hybridization, and in situ hybridization. In addition, in vivo techniques for detecting biomarker proteins include introducing to the individual a labeled antibody to the protein or fragment thereof. For example, antibodies can be labeled with a radioactive label that is present in the individual and can be detected by standard imaging techniques at the location of 144535.doc • 52· 201023852. The general principles of such shifting and predictive assays include preparing a sample or reaction mixture that may contain biomarkers and probes under appropriate conditions for a time sufficient to allow the biomarker to interact with the probe and the time of binding thereby forming The complex that should be removed and/or detected in the mixture. These checks can be made in a variety of ways. For example, one method of performing this assay involves anchoring a biomarker or probe to a solid support (also referred to as a substrate) and detecting target organisms anchored to the solid phase at the end of the reaction. Label/probe complex. In one embodiment of the method, the individual sample for which the presence and/or concentration of the biomarker is to be assayed can be anchored to the carrier or solid support. In another embodiment, the opposite may be the case where the probe can be anchored to the solid phase and the individual sample can be reacted as a non-anchored component of the assay. There are several established methods for anchoring assay components to a solid phase. It includes, but is not limited to, a biomarker or a probe molecule immobilized via binding of biotin to streptavidin. The biotinylated assay components can be prepared from biotin seven (9) via butyl amides using techniques known in the art (eg, biotin label kit, pierce Chemicals, Rockford, 111.). And fixed in a 96-well plate coated with streptavidin (Pierce

Chemical) in the hole. In certain embodiments, the surface with the immobilized assay component can be prepared in advance and stored. Other suitable carriers or solid supports for such assays include any material capable of binding to the class of molecules to which the biomarker or probe belongs. Well known supports or carriers include, but are not limited to, glass, polystyrene, polyester, polypropylene, nylon, polyethylene, polydextrose, amylase, 144535.doc • 53- 201023852 natural and modified cellulose 'polypropylene Thin amines, gabbros and magnetite. To be assayed by the above method, a non-fixed component is added to the solid phase. The second component is anchored on the solid phase. After completion of the reaction, the uncomplexed component can be removed (e.g., by washing) under conditions such that any of the formed complexes are still immobilized on the solid phase. Detection of the biomarker/probe complex anchored to the solid phase can be accomplished in a variety of ways as described herein. In one embodiment, if the probe is a non-missing assay component, the assay is detected and read, which can be directly or indirectly labeled with detectable labels as described herein and familiar to those skilled in the art. It is also possible to directly detect biomarker/probe complex formation without further manipulation or labeling of any component (biomarker or probe), for example by using a fluorescent energy transfer technique (ie FET, see for example Lakowicz et al. U.S. Patent No. 5,63,169; and Stavrianopoulos et al., U.S. Patent No. 4,868 '1〇3). Selecting a fluorophore label on the donor molecule such that upon excitation with incident light of the appropriate wavelength, the fluorescent energy emitted by it will be absorbed by the fluorescent label on the acceptor molecule, which in turn is due to the absorbed energy. Can emit fluorescent light. Alternatively, the donor protein molecule may utilize only the natural fluorescent energy of the tryptophan residue. A label that emits light of a different wavelength is selected such that the acceptor molecule label can be distinguished from the donor. Since the energy transfer efficiency between the markers is related to the distance separating the molecules, the spatial relationship between the molecules can be assessed. In the case of a binding between molecules, the fluorescent emission of the receptor molecule label in the assay should be the most A. The FET binding event should be measured by standard fluorometric detection methods well known in the art (e.g., using a fluorometer). In another embodiment, the ability of the assay probe to recognize a biomarker can be performed by utilizing, for example, an immediate biomolecule interaction analysis (BIA; for example, see 144535.doc 201023852 for labeling any assay component (probe or biomarker); Technical implementation of Sjolander, S. and Urbaniczky, C., 1991, Anal. Chem. 63: 2338-2345 and Szabo et al., 1995, Curr. Opin. Struct. Biol. 5: 699-705). As used herein, "ΒΙΑ" or "surface plasmon resonance" refers to techniques for studying immediate biospecific interactions (e.g., BIAcore) without the need to label any reactants. A change in the mass of the binding surface (indicating a binding event) causes a change in the refractive index of the light in the vicinity of the surface (the optical phenomenon of surface plasma resonance (SPR)), producing a detectable signal that can be used as an indication of an immediate response between the biomolecules. Alternatively, in another embodiment, similar diagnostic and predictive assays can be performed in which the biomarkers and probes act as solutes in the liquid phase. In this assay, complex biomarkers and probes are separated from uncomplexed components by any of a variety of standard techniques including, but not limited to, differential centrifugation, chromatography, electrophoresis, and immunosuppression. . In the case of differential centrifugation, the biomarker/probe complex can be separated from the uncomplexed assay component via a series of centrifugation steps due to different settling equilibriums based on the different sizes and densities of the complex (see, for example, Rivas, G_). And Minton, A. P., 1993, Trends Biochem Sci. 18(8): 284-7). Standard chromatography techniques can also be used to separate the composite molecules from the uncomplexed molecules. For example, gel filtration chromatography is based on size and separates the molecules by using a suitable gel filtration resin in a column format, for example, to separate relatively large complexes from relatively small uncomplexed components. Similarly, the biomarker/probe complex can be used to distinguish the complex from the uncomplexed component using relatively different charge characteristics compared to the uncomplexed component, e.g., via the use of ion 144535.doc - 55. 201023852 to exchange the chromatography resin. Such resins and chromatographic techniques are well known to those skilled in the art (see, for example, Heegaard, NH, 1998, J. Mol. Recognit. Winter 11(1-6): 141-8; Hage, DS and Tweed, SAJ Chromatogr B Biomed Sci Appl, October 10, 1997; 699(1-2): 499-525). Gel assays can also be used to separate the composite assay component from the unbound component (see, for example, Ausubel et al., eds. Current Protocols in Molecular Biology, John Wiley &amp; Sons, New York, 1987-1999). In this technique, the protein or nucleic acid complex is based on, for example, size or charge separation. To maintain binding interactions during electrophoresis, non-denaturing gel matrix materials and conditions in the absence of a reducing agent are typically utilized. The appropriate conditions for a particular assay and its components are well known to those skilled in the art. In another embodiment, the amount of biomarker mRNA in a biological sample can be determined by in situ and in vitro methods using methods known in the art. The term "biological sample" is intended to include tissue isolated from an individual (including but not limited to biopsy tissue), cells, biological fluids and their isolates, as well as tissues, cells and fluids present in the individual. Many performance detection methods use isolated RNA. For in vitro methods, RNA can be purified from tumor cells using any RNA isolation technique not selected for mRNA isolation (see, for example, Ausubel et al., eds. Current Protocols in Molecular Biology, John Wiley &amp; Sons, New York 1987-1999). In addition, a large number of tissue samples can be readily processed using techniques well known to those skilled in the art, such as the single step RNA isolation method of Chomczynski (1989, U.S. Patent No. 4,843,155). The isolated mRNA can be used for hybridization or amplification assays including, but not limited to, 144535.doc-56-201023852 Southern or Northern analysis, polymerase chain reaction analysis, and probe arrays. A diagnostic method for detecting mRNA levels involves contacting the isolated mRNA with a nucleic acid molecule (probe) that hybridizes to the mRNA encoded by the detection gene. The nucleic acid probe can be, for example, a full-length cDNA or a portion thereof, such as an mRNA or genome that is at least 7, 15, 30, 50, 100, 250, or 500 nucleotides in length and sufficient to encode a biomarker as described herein under stringent conditions. DNA-specific hybridized oligonucleotides. The determination of appropriate stringency can be identified by routine testing according to conventional molecular techniques. Other suitable probes are suitable for use in the diagnostic assays described herein. Hybridization of the mRNA with the probe indicates that the biomarker in question is expressed. In one form, the mRNA is immobilized on a solid surface and is in contact with the probe, for example, by operating the isolated mRNA on an agarose gel and transferring the mRNA from the gel to a membrane such as nitrocellulose. In another form, the probe is immobilized on a solid surface and the mRNA is contacted with the probe, for example in an Affymetrix gene wafer array according to the manufacturer's instructions. Those skilled in the art can readily modify known mRNA detection methods for detecting the amount of mRNA encoded by the biomarkers described herein. Another method for determining the amount of mRNA biomarker in a sample includes, for example, reverse transcriptase-polymerase chain reaction (RT-PCR; for example, the experimental examples described in Mullis, 1987, U.S. Patent No. 4,683,202), ligase Chain reaction (eg, Barany, 1991, Proc. Natl. Acad. Sci. USA, 88: 189-193), autonomous sequence replication (eg, Guatelli et al, 1990, Proc. Natl. Acad. Sci. USA 87: 1874-1878 ), transcriptional amplification systems (eg, Kwoh et al, 1989, Proc. Natl. Acad. Sci. USA 86: 1173-1177), Q-beta replicase (Lizardi et al, 1988, 144535.doc • 57-201023852

Bio/Technology 6:1197), Rolling Ring Replica 1 匕 Rainbow (1) et al., U.S. Patent No. 5,854,033) or any other nucleic acid amplification process performed by a nucleic acid amplification method' is then detected using techniques well known to those skilled in the art. Amplified molecule. These township protocols are particularly useful for extracting such molecules in the presence of a very small number of nucleic acid molecules. An amplification primer as used herein is defined as a pair of nucleic acid molecules that can bind to a 5, or 3, region of a gene (either positive and negative, respectively or vice versa) and contain short regions therebetween. In general, the amplification primer is about 10 to 30 nucleotides in length and has a side length of about 50 to 200 nucleotides. The appropriate reagents are used under appropriate conditions such that the nucleic acid molecule comprising the nucleotide sequence flanked by the primer can be amplified. For in situ methods, there is no need to isolate mRNA from tumor cells prior to detection. In such methods, cells or tissue samples are prepared/treated using known histological methods. The sample is then immobilized on a support (usually a glass slide) and subsequently contacted with a probe that hybridizes to the mRNA encoding the biomarker. The determination can be made based on the corrected performance of the biomarker instead of the absolute performance based on the biomarker. The amount of expression of the biomarker is corrected by comparing the performance of the biomarker with the performance of the non-biomarker gene (e.g., a housekeeping gene of constitutive expression) to correct the amount of expression. Suitable genes for correction include housekeeping genes such as actin genes or epithelial cell specific genes. This correction allows comparison of the amount of expression of one sample (e. g., a patient sample) with another sample (e.g., a non-tumor sample) or between samples of different sources. Or 'the amount of performance can be provided in the form of relative performance. For the determination of the relative amount of biomarkers 144535.doc -58- 201023852 (eg, mesenchymal biomarkers), one or more than 10, 20 or more, 30 or more, The amount of biomarker expression of 4 or more or more than 50 or more normal cell isolate samples relative to the cancer cell isolate sample, followed by determination of the amount of expression of the sample in question. The average performance of each assay gene in a larger number of samples was determined and used as the baseline performance of the biomarker. The biomarker performance (absolute performance) of the test sample β» was then divided by the average performance value obtained for the biomarker. This provides relative performance. In another embodiment, the biomarker protein is detected. One of the agents for detecting a biomarker protein is an antibody or a fragment thereof capable of binding the protein, such as a detectably labeled antibody beta antibody, which may be a plurality of strains or a monoclonal antibody. An intact antibody or antigen-binding fragment thereof (e.g., Fab, F(ab,)2, Fv, scFv, single binding chain polypeptide) can be used. The term "marker" with respect to a probe or antibody is intended to encompass the direct labeling of a probe or antibody by coupling a detectable substance to a probe or antibody (ie, physically linked), and by direct labeling with another reagent. The reaction indirectly labels the probe or antibody. Examples of indirect labeling include detection of a first antibody using a fluorescently labeled secondary antibody, and labeling the DNA probe with a biotin end such that it can be detected with a fluorescently labeled streptavidin. Proteins can be isolated from tumor cells using techniques well known to those skilled in the art. The protein separation method used may be, for example, Harlow and Lane (Harlow and Lane, 1988, Antibodies: A Laboratory Manual, Cold).

Method described in Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.). 144535.doc -59- 201023852 Various forms can be used to determine whether a sample contains a protein that binds to a given antibody. Examples of such forms include, but are not limited to, enzyme immunoassay (EIA), radioimmunoassay (RIA), western blotting Analysis, immunohistochemistry, and enzyme-linked immunosorbent assay (ELISA). Those skilled in the art can readily modify known protein/antibody detection methods for determining whether a tumor cell exhibits a biomarker. In the form, an antibody or antibody fragment or derivative can be used in a method such as Western blotting or immunofluorescence to detect the expressed protein. In such use, the antibody or protein can be immobilized on a solid support. Suitable solid supports or carriers include any of the agents capable of binding an antigen or antibody. Well known supports or carriers include glass, polystyrene, polypropylene, polyethylene, dextran, symmetry, phosphatase, natural and modified cellulose, polypropylene guanamine, gabbro and magnetite. We should be aware of or can identify other suitable carriers for binding antibodies or antigens, and should be able to modify the support to be suitable for use in the methods of the invention. For example, proteins isolated from tumor cells can be manipulated on polypropylene guanamine gel electrophoresis and immobilized on a solid support such as nitrocellulose. The support can then be washed with a suitable buffer and then treated with a detectably labeled antibody. The solid support can then be washed a second time with buffer to remove unbound antibody. The amount of bound label on the solid support can then be measured by means of a known means. For ELISA assays, specific binding pairs can be of the immunological or non-immune type. Immunospecific binding pairs are exemplified by antigen-antibody systems or hapten/anti-anti-antigen systems. Mention may be made of luciferin/anti-luciferin, dinitrophenyl/anti-nitrophenyl, biotin/avidin, peptide/antipeptide and analogues thereof:: 144535.doc 201023852 Sexual binding pair Antibody members can be produced by conventional methods well known to those skilled in the art. Such methods include immunizing an antigen member with a specific binding pair. If the antigen binding member of the specific binding pair is non-immunogenic, such as a semi-antigen, it can be covalently coupled to the carrier protein to render it immunogenic. Non-immune binding pairs include systems in which the two components have a natural affinity for each other but are not antibodies. Exemplary non-immune pairs are biotin _ streptavidin, intrinsic factor-vitamin B12, folate-folate binding protein and analogs thereof. Antibodies can be covalently labeled with members of a specific binding pair using a variety of methods. The selection method based on the nature of the specific binding pair member, the type of linkage desired, and the tolerance of the antibody to various binding chemicals. Biotin can be covalently coupled to an antibody by using a commercially available reactive derivative. Some of them are biotin_N_hydroxybutanediamine, which binds to an amine group on a protein; biotin, which binds to a carbohydrate moiety via a rabbit diamine, binds to a thiol; and biotin An enediamine imine and an iodoethylidene biotin which bind to a sulfhydryl group. Luciferin can be coupled to a protein amine group using luciferin isothiocyanate. The dinitrophenyl group can be coupled with a protein amine group using 2,4-dinitrophenyl sulfate or 2,4-dinitrofluorobenzene. Other standard binding methods can be used to couple individual antibodies to specific binding partners, including dialdehydes, carbodiimide couplings, homofunctional crosslinking, and heterobifunctional crosslinking. The carbodiimide coupling is a method effective for coupling a carboxyl group of one substance to an amine group of another substance. The carbodiimide coupling can be facilitated by using the commercially available reagent 1-ethyl-3-(dimethyl-aminopropyl)-carbodiimide (EDAC). Homobifunctional crosslinkers (including difunctional quinones and difunctional N_hydroxy 144535.doc • 61 - 201023852 dimethyl imidate) are commercially available and are used to make an amine on one substance with another Substance amino group coupling. Heterobifunctional crosslinkers are reagents having different functional groups. The most common commercially available heterobifunctional crosslinkers have an amine reactive hydroxy hydroxy dimethyl imidate as a monofunctional group and a sulfhydryl reactive group as a second functional group. The most common sulfhydryl reactive groups are maleimide, pyridyl disulfide and reactive halogen. One of the functional groups may be a photoactive aryl carbite which reacts with various groups after irradiation. An antibody that specifically binds to a detectably labeled antibody or a detectably labeled member can be prepared by coupling with a reporter, which can be a radioactive synonym, an enzyme, a fluorescent substance, a chemiluminescent substance, or Electrochemical substance. The two commonly used radioisotopes are 125; 1 and 4. Standard radioisotope labeling procedures include the gas amine T, lactoperoxidase and the Bolton-Hunter method for the mouth and the reductive methylation for 3H. The term "debt-testing marker" refers to The molecule is labeled in a definite manner such that it can be readily detected by the intrinsic enzymatic activity of the label or by binding to another label which is readily detectable by the other component. Enzymes suitable for use in this method include (but; limited to) horseradish peroxidase, avidin luciferase, beta-galactosidase, glucose oxidase, luciferase (including firefly luciferase and jellyfish) (reniUa) luciferase), beta-lactamase, glandular enzyme, green fluorescent protein (GFP) and lysozyme. The coupling of an antibody to a member of a specific binding pair by using the above-mentioned two-chain, carbodiimide coupling, homobifunctional crosslinking agent and heterobifunctional crosslinking agent facilitates enzymatic labeling. The selected labeling method depends on the enzyme and the available functional groups on the substance to be labeled and the tolerance of the two to the binding conditions. The labeling method used may be (but not limited to) 144535.doc -62- 201023852. One of the methods 'These methods include Engvall and Pearlarm, Immunochemistry 8, 871 (1971);

Temynck' Immunochemistry 8, 1175 (1975); Ishikawa et al, J. Immunoassay 4(3) 209.327 (1983); and Jabl〇nski, AnaL Biochem. 148:199 (1985). Labeling can be achieved by indirect methods, such as using spacers or other members of a specific binding pair. An example of this is the detection of biotinylated antibodies with unlabeled streptavidin and biotinylated enzymes, wherein antibiotics and biotinylated enzymes are added sequentially or simultaneously. Thus, the antibody used for detection can be directly detectable by a reporter or indirectly detectable by a first member of a specific binding pair. If the antibody is coupled to the first member of the specific binding pair, the antibody-first member of the specific binding complex is detected by reacting the binding member with the labeled or unlabeled second member. Furthermore, an unlabeled detection antibody can be detected by reacting an unlabeled antibody with a labeled antibody specific for the unlabeled s-antibody. In this case, "detectable label" as used above means an antigenic determinant, and an antibody specific for an unlabeled antibody can be bound by the epitope. The anti-antibody can be labeled directly or indirectly using any of the methods described above. For example, the 5' anti-antibody can be coupled to biotin, and biotin is detected by reaction with the above-described anti-streptavidin-horseradish peroxidase system. Thus, in one embodiment, biotin is used. The biotinylated antibody is then reacted with a streptavidin-horseradish peroxidase complex. O-phenylenediamine, 4-chloro-naphthol, tetramethylbenzidine (TMB), ABTS, BTS or ASA can be used for color detection. 144535.doc -63- 201023852 In an immunoassay format, a forward sandwich assay is used where the capture reagent has been immobilized on the surface of the support using conventional techniques. Suitable supports for use in the assay include synthetic polymeric supports such as polypropylene, polystyrene, substituted polystyrene (eg aminated or carboxylated polystyrene), polyacrylamide, polyamine, polystyrene , glass beads, agarose or nitrocellulose. One or more biomarkers may also be assessed using a combination of two or more of the above assays. The values obtained from the test and/or control samples can be statistically processed using any suitable statistical analysis method to establish a suitable baseline content using standard methods for establishing baseline content values in the art. Statistical significance can be readily determined as described further in, for example, U.S. Patent Application Serial No. 11/781,946. By way of example only, 'in one embodiment' the statistical significance is at least p &lt; 0. Therapeutic Proliferative Diseases Described herein are compounds, pharmaceutical compositions, and methods for treating a patient suffering from a proliferative disorder by administering alone or with one or more other active ingredients (eg, an anticancer agent) and/or therapeutic therapy ( For example, surgery) is achieved by administering an effective amount of a catechol butane described herein (i.e., a single compound of a dual kinase inhibitor). This application is generally directed to a method of treating a disease using catechol butane (or a derivative thereof) as described herein. For example, it relates to catechol butane NDGA or a salt, solvate, isomer, tautomer, metabolite, analog or prodrug thereof for treating proliferative by inhibiting IGF-1R and EGFR Use in disease. 144535.doc • 64· 201023852 Provided herein is a method of treating a disease comprising administering an effective amount of a pharmaceutical compound capable of inhibiting the activity of tyrosine kinase of IGF-1R and EGFR, wherein the pharmaceutical compound is a catechol described herein Butane (i.e., a compound that is a dual kinase inhibitor). • Also provided herein is a method of treating an individual's disease that has developed resistance to one or more EGF-R inhibitors or IGF-1R inhibitors, comprising administering an effective amount of a tyrosine kinase capable of inhibiting IGF-1R and EGFR An active pharmaceutical compound wherein the pharmaceutical compound is catechol butane (i.e., a dual kinase inhibitor). ® In one embodiment, the disease is a proliferative disease. Proliferative diseases include, but are not limited to, malignant, premalignant or benign cancers. Cancers to be treated using the disclosed methods include, for example, solid tumors, lymphomas, or white disease. In one embodiment, the cancer can be, for example, a brain tumor (eg, a malignant, pre-malignant or benign brain tumor such as a glioblastoma, astrocytoma, a meningomoma, a neuroblastoma or a peripheral neuroectoderm) Tumors, carcinomas (eg gallbladder, bronchial, basal cell carcinoma (basai φ cel1 carcinoma), adenocarcinoma, squamous cell carcinoma, small cell carcinoma, large cell undifferentiated carcinoma, adenoma, cystadenoma, etc.) Basal cell tumor (basali〇rna), teratoma, retinoblastoma, choroidal melanoma, seminoma, sarcoma (eg Ewing's sarcoma, rhabdomyosarcoma, craniopharyngioma, osteosarcoma, chondrosarcoma, Muscle, liposarcoma, fibrosarcoma, leiomyosarcoma, Askin's tumor, lymphosarcoma, neurosarcoma, Kaposi's sarcoma, cutaneous fibrosarcoma, vascular sarcoma, etc.), plasmacytoma, head and neck tumors (eg mouth, throat) , nasopharyngeal, esophageal, etc.), liver tumor, kidney tumor, renal cell tumor, squamous cell carcinoma, uterine tumor, bone tumor, prostate tumor, milk 144535.doc -65- 201023852 Tumors (including but not limited to, Her2- and/or ER- and/or PR-tumor breast tumors), bladder tumors, pancreatic tumors, endometrial tumors, squamous cell carcinomas, gastric tumors, glial tumors , colorectal tumor, testicular tumor, colon tumor, rectal tumor, ovarian tumor, cervical tumor, eye tumor, central nervous system tumor (such as primary CNS lymphoma, spinal tumor, brain stem glioma, pituitary adenoma Etiology, thyroid neoplasms, lung tumors (eg non-small cell lung cancer (NSCLC) or small cell lung cancer), leukemia or lymphoma (eg cutaneous T-cell lymphoma (CTCL), non-skin peripheral T-cell lymphoma, with pro-human T Lymphoma associated with cellular lymphovirus (HTLV) (such as adult tau cell leukemia/lymphoma (ATLL)), sputum cell lymphoma, acute non-lymphocytic leukemia, chronic lymphocytic leukemia, chronic osteomyelitis, acute bone marrow Leukemia, lymphoma, and multiple myeloma, non-Hodgkin's lymphoma, acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia ( CLL), Hodgkin's lymphoma, Burkitt's lymphoma, adult T-cell leukemia/lymphoma, acute myeloid white disease (AML), chronic myelogenous leukemia (CML) or hepatocellular carcinoma, etc., multiple Myeloma, skin tumors (eg basal cell carcinomas, squamous cell carcinoma, melanoma (such as malignant melanoma, cutaneous melanoma or intraocular melanoma), protuberous cutaneous fibrosarcoma, Merkel cell carcinoma Or Kaposi's sarcoma, gynecological tumors (such as uterine sarcoma, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vaginal cancer, etc.), Hodgkin's disease, small intestine cancer, endocrine system cancer (such as 曱Tumors, mesothelioma, adrenal cancer, etc., mesothelioma, urethral cancer, penile cancer, Golling's syndrome-related tumors (eg, neuroblastoma, meningococcal tumor, etc.), swelling of unknown origin 144535.doc -66 - 201023852 Tumor, or any of them. In another embodiment, the cancer is a lung tumor, a breast tumor, a colon tumor, a colorectal tumor, a head and neck tumor, a liver tumor, a prostate tumor, a glioma, a glioblastoma multiforme, an ovarian tumor, or a thyroid tumor, Or the transfer of either. In another embodiment, the cancer is an endometrial tumor, a bladder tumor, multiple myeloma, melanoma, renal tumor, sarcoma, cervical tumor, leukemia, and neuroblastoma. The tumor provided herein can be a primary tumor or a metastatic tumor. Cancer can also be epithelial-based cancer. In one embodiment, the tumor cells can exhibit EGFR. In another embodiment, the tumor cells can exhibit IGF·丨R. In another embodiment, the tumor cells can exhibit EGFR and IGF-1R. Provided herein are methods of treating malignant, pre-malignant or benign cancer comprising an effective amount of a pharmaceutical compound capable of inhibiting the activity of phosphatase of IGF-IR and EGFR, wherein the pharmaceutical compound is catechol butane (also It is a single compound of a dual kinase inhibitor). Provided herein are methods of selecting an individual for treatment with catechol butyl ketone capable of inhibiting tyrosine kinase activity of IGF-IR and EGF-R, wherein the individual is identified as having IGF-1R, EGFR, or both. The control group content was twice the baseline content or baseline content. In one aspect, an individual has previously been treated with an EGFR inhibitor or an IGF-IR inhibitor. In another aspect, the individual may be treated with at least one tyrosine kinase inhibitor (eg, only an EGFR inhibitor or only an IGF-IR inhibitor or an IGF-IRR and 144535.doc-67-201023852 EGFR inhibitor) Resistance. Provided herein are methods for degrading cancer cells of epithelial origin, inhibiting the growth of such cancer cells, or killing such cancer cells, comprising causing such cells to degrade, inhibit the growth of such cancer cells, or kill such cancers The amount of cells is contacted with the tea phenol butane. A method for inhibiting an increase in tumor size in an individual, reducing tumor size in an individual, reducing tumor proliferation in an individual, or preventing tumor proliferation in an individual, comprising administering to the individual an effective amount of a catechol butane described herein Inhibit tumor size increase, reduce tumor size, reduce tumor proliferation or prevent tumor proliferation. In some cases, treating a tumor involves arresting the symptoms, i.e., by treating the patient, so that the cancer does not deteriorate and prolongs the patient's survival. Symptoms of one or more multiple time points of the patient may be assessed, including before, during, and after treatment therapy. Treatment may improve the condition of the individual and may be assessed by determining whether one or more of the following events have occurred: reduced tumor size, decreased tumor cell proliferation, decreased cell number, decreased neovascularization, and/or increased cell death. The occurrence of one or more may lead to partial or total removal of cancer and prolong the survival of the patient in some cases. Or, 'In the late stages of cancer, treatment may arrest the disease, produce a better quality of life and/or prolong survival. Other methods of assessing treatment are known in the art and are encompassed herein. It is to be understood that the cancer therapies described herein can be assessed using the classification and grading systems described herein. Additionally, other fractionation protocols are known in the art and can be used in conjunction with the methods described herein. By way of example only, the TNM classification of malignant tumors can be used as a cancer grading system to describe the cancer course in a patient 144535.doc -68 - 201023852 degrees. T describes the size of the tumor and whether it has invaded nearby tissue, n describes the regional lymph nodes involved and describes the distant cancer metastasis. TNM is provided by the International Union Against Cancer (UICC) and is affiliated with the American Joint Committee on Cancer (American Joint)

Committee on Cancer, A JCC) and the International Federation of Gynecology and Obstetrics (FIGO). We should understand that not all tumors have a TNM classification, such as a brain tumor. In general, T (a is (0) 1-4) is measured as the size or directness of the primary tumor. N(0-3) refers to the extent of diffusion to regional lymph nodes. · N〇 means that there are no tumor cells in regional lymph nodes. N1 means that tumor cells spread to the closest or a few regional lymph nodes. N2 means that tumor cells spread to N1 and N3. The degree of N3 means that the tumor cells spread to the most distal or many regional lymph nodes. Μ(〇/ι) refers to the presence of cancer metastasis: M〇 means that there is no distant cancer metastasis' Ml means that the distant organ (beyond the regional lymph node) has metastasized. Other parameters can also be applied. G(1 -4) refers to the level of cancer cells (i.e., if it looks similar to normal cells, it is a low grade, and if it appears to be poorly differentiated, it is a high grade). R (0/1/2) refers to the C〇mpleteness of the operation (ie, the resected border contains no cancer cells or cancer cells). L (〇 / l) refers to invading the lymphatics ^ v (〇 / 1) refers to the invasion of the vein. c(1_4) refers to the regulation parameter (m〇difier) of v-certainty (quality). In one aspect, this article provides a method for treating breast cancer, such as breast tube in breast duct tissue. Cancer, breast cancer of Her2- and/or ER- and/or PR·cancer 0 144535.doc • 69- 201023852 There are several breast cancers that can be treated by the methods described herein. Lobular carcinoma in situ and ductal carcinoma in situ are breast cancers that have been produced in the lobules and ducts but have not spread to the adipose tissue around the breast or other areas of the body. Infiltrating (or invasive) lobular and ductal carcinoma are cancers that have been produced in the lobule and duct, respectively, and have spread to the adipose tissue of the breast and/or other parts of the body. Other breast cancers that would benefit from treatment by such methods are medullary carcinoma, glial cancer, tubular cancer, and inflammatory breast cancer. In one embodiment, 'breast cancer is graded according to the TNM system. The prognosis and grading results are closely related in clinical trials and clinical practice, and patients are also assigned to each therapy using grading. In short, the classification information is as follows: τχ: The primary tumor cannot be assessed. T0: No evidence of cancer. Tis: carcinoma in situ 'no invasion; T1: 2 cm or less than limbs; T2: tumors larger than 2 cm but not more than 5 cm; T3: tumors larger than 5 cm; T4: growing to the chest wall or skin A tumor of any size, or an inflammatory breast cancer. NX: Cannot assess nearby lymph nodes. NO: The cancer has not spread to the area. Lymph nodes ^ N1 : The cancer has spread to 1 to 3 axillary lymph nodes or 1 internal milk lymph node. N2: Cancer has spread to 4 to 9 axillary lymph nodes or multiple internal milk lymph nodes. N3: One of the following applies: cancer has spread to 1 or more axillary lymph nodes 'or cancer has spread to the subclavian lymph nodes' or lymph nodes that have spread to the clavicle, or cancer involves axillary lymph nodes and has an increase Intramalignant lymph nodes, or cancer involving 4 or more axillary lymph nodes' and a small amount of cancer found in the internal mammary lymph nodes in sentinel lymph node biopsy. 0 144535.doc •70· 201023852 MX: Cannot assess distal spread (cancer The existence of transfer). M〇: no distal diffusion. Ml: has spread to the distal organs (excluding the supraclavicular lymph nodes). The methods provided herein can provide a beneficial effect to breast cancer patients by administering catechol butane or administering catechol butane with one or more anti-cancer therapies. Ovarian Cancer In another aspect, a method of treating ovarian cancer, including an epithelial ovarian tumor, is provided herein. Preferably, the method treats ovarian cancer selected from the group consisting of adenocarcinoma in the ovary and adenocarcinoma that has migrated from the nest to the abdominal cavity. The methods provided herein can provide a beneficial effect to ovarian cancer patients by administering catechol butane or administering catechol butane with one or more anti-cancer therapies. Cervical cancer In another aspect, the method treats cervical cancer, preferably adenocarcinoma in the cervical epithelium. There are two main types of this cancer: squamous cell carcinoma and adenocarcinoma. The former constitutes approximately 8〇_9〇% of all cervical cancer and is produced in the junction of the outer cervix (the part closest to the vagina) and the endocervix (the part closest to the uterus). The latter is produced in the glandular cells that produce mucus in the endocervix. Some cervical cancers have the characteristics of both and are called adenosquamous carcinoma or mixed type cancer. The methods provided herein can provide a beneficial effect to cervical cancer patients by administering a combination of catechins 15 or administering catechins and/or anti-cancer therapies. Prostate Cancer 144535.doc • 71· 201023852 In another form, a method of treating prostate cancer is provided herein, preferably a prostate cancer selected from the group consisting of adenocarcinoma or adenocarcinoma that has migrated to the bone. Prostate cancer is produced in the prostate organ of the male-part of the urethra. The prostate has several cell types, but 99% of the tumors are adenocarcinomas produced in the glandular cells responsible for producing semen. There are two common protocols for grading prostate cancer. The most common protocol is the TNM system, which evaluates the extent of the lymph nodes involved in the size of the tumor and any cancer metastasis (distal spread). Like many other cancers, another option for use in four (four) is the Whitmore-Jewett stage. Briefly, the 'stage I disease is a cancer found in a small portion of the sample (4) when the prostate tissue is removed for other reasons, such as benign prostatic hypertrophy, and the cells are extremely similar to normal cells and the finger feels normal gland. In the second phase, more prostate is involved, and a mass can be felt in the gland. In stage III, the tumor has spread from the prostatic sac and a mass can be felt on the surface of the gland. In stage IV disease, the tumor has invaded nearby structures or has spread to lymph nodes or other organs. Grading is based on the cellular contents and tissue architecture (Gleason) from the biopsy, which estimates the disease's rupture potential and the final prognosis. The methods provided herein can provide a beneficial effect to prostate cancer patients by administering catechol butane or administering catechol butane with one or more anti-cancer therapies. In another aspect, the present invention provides a method for treating pancreatic cancer, preferably 144535.doc -72· 201023852 from the following pancreatic cancer: epithelioid carcinoma in the pancreatic duct tissue and adenocarcinoma in the pancreatic duct . The most common type of pancreatic cancer is adenocarcinoma, which occurs in the inner layer of the pancreatic duct. The methods provided herein can provide beneficial effects to pancreatic cancer patients by administering catechol butane or administering catechol butane with one or more anti-cancer therapies. » Breast Cancer In another aspect, the present invention provides a method of treating bladder cancer, preferably transitional cell carcinoma in the bladder. Bladder cancer is a tumor in urothelial carcinoma (transitional cell carcinoma) or in the urethral epithelial cells of the bladder inner layer. The remaining cases of bladder cancer are squamous cell carcinoma, adenocarcinoma and small cell carcinoma. Urethral epithelial cancer is non-invasive or invasive and papillary or flat, and there are several subtypes of urothelial carcinoma. Non-invasive tumors are in the innermost layer of the bladder, the urethral epithelium, and invasive tumors have spread from the urethral epithelium to the deeper layers of the main muscle wall of the bladder. A papillary urothelial carcinoma of the genital area is a slender finger-like projection that bisects into the bladder, and also grows outward into the wall of the bladder. Non-invasive milk φ Head urethral epithelial tumors grow toward the center of the bladder. Non-invasive flat urothelial tumors (also known as flat-type carcinoma in situ) are confined to the cell layer closest to the hollow portion of the bladder, while invasive flat urothelial carcinoma invades the deeper layers of the bladder, especially the muscle layer. The methods provided herein can provide a beneficial effect to bladder cancer patients by administering catechol butane or administering catechol, or a combination of various anti-cancer therapies. Acute myeloid leukemia In another aspect, the present invention provides a method for treating acute myeloid leukemia (aml) 144535.doc • 73-201023852, preferably acute promyelocytic leukemia in peripheral blood. AML begins in the epiphysis but spreads to other parts of the body, including the lymph nodes, liver, spleen, central nervous system, and testicles. Acute means that it develops rapidly and can be fatal if left untreated within a few months. AML is characterized by immature bone marrow cells, usually granulocytes or monocytes, which continue to regenerate and accumulate. There are other types of leukemia that can also be treated by the methods provided herein, including but not limited to acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic osteomyelitis, hairy cell leukemia, myelodysplasia And spinal cord hyperplasia. The methods provided herein can provide a beneficial effect to leukemia patients by administering catechol butane or administering catechol butane with one or more anti-cancer therapies. Lung cancer is in another aspect. Herein, a method of treating lung cancer is provided. The most common type of lung cancer is non-small cell lung cancer (NSCLC), which accounts for about 80_85% of lung cancer and is classified into squamous cell carcinoma, adenocarcinoma, and large cell undifferentiated carcinoma. Small cell lung cancer accounts for 15-20% of lung cancer. Lung cancer grade is an assessment of the extent to which cancer has spread from its original source. It is an important factor affecting the prognosis and potential therapy of lung cancer. Cell lung cancer is classified as “-A” (best prognosis) to IV (“four”: worst prognosis). If small cell lung cancer is confined to one and a half of the chest and within the scope of a single radiotherapy area, it is classified as a limited stage; otherwise it is classified as an extended stage ° 144535.doc •74- 201023852 Lung cancer Classification can be performed using EUS (Endoscopic Ultrasonic) or TNM. Graded to assess a portion of a patient with non-small cell lung cancer. These patients are graded as part of the process of considering prognosis and therapy. AJCC recommends ΤΝΜ grading and then further grouping. Primary tumor (Τ): ΤΧ: The primary tumor cannot be assessed, or malignant cells are present in saliva or bronchoalveolar lavage, but not visible during imaging or bronchoscopy;

Tis: carcinoma in situ. T0: No evidence of primary tumor. T1: The largest tumor size is less than 3 cm, surrounded by the lung or visceral thoracic cavity and the bronchoscopy did not invade the main bronchus. Τ 2. Tumors with any of the following characteristics: maximum size greater than 3 cm; diffusion to the main bronchus (but more than 2 cm from the protuberance) and obstructive pneumonia (but not the entire lung). T3: Tumor with any of the following characteristics: invasion of the chest wall, diaphragm, mediastinal pleura or parietal pericardium; diffusion into the main bronchus within 2 cm of the bulge, but not involving the protuberance; and obstruction of the entire lung Pneumonia. T4. A tumor having any of the following characteristics: invasion of the mediastinum, heart, large blood vessels, trachea, esophagus, vertebrae or carina; tumor nodules isolated in the same lobe; and malignant pleural effusion. Lymph node (N): NX: no lymph node assessment, NO: no lymph node involvement; N1: metastasis to the ipsilateral bronchial or ipsilateral hilar lymph node; N2: metastasis to the ipsilateral mediastinum or subcarinal lymph node; and N3: to any The following site 144535.doc 75- 201023852 metastasis: ipsilateral supraclavicular lymph nodes; ipsilateral scalene muscle lymph nodes; and contralateral lymph nodes. Distal cancer metastasis (Μ): MX: unable to assess distant cancer metastasis; M〇: no distant cancer metastasis; and Ml: distal cancer metastasis. The methods provided herein can provide a beneficial effect to lung cancer patients by administering catechol butane or administering catechol butane with one or more anti-cancer therapies. Skin Cancer In another aspect, a method of treating skin cancer is provided herein. There are several types of cancer that start with the skin. The most common types are basal een carcinoma and squamous cell carcinoma, which are non-melanoma skin cancers. Actinic keratosis is a skin disease that sometimes develops into squamous cell carcinoma. Non-melanoma Skin cancer rarely spreads to other parts of the body. Melanoma (the rarest form of skin cancer) is likely to invade nearby tissues and spread to other parts of the body. The methods provided herein can provide a beneficial effect to skin cancer patients by administering catechol butane or administering catechol butane with one or more anti-cancer therapies. Eye Cancer 'Retinoblastoma In another aspect, a method of treating ocular retinoblastoma is provided herein. Retinoblastoma is a malignant tumor of the retina. Although retinoblastoma can occur at any age, it is most often seen in young children, usually before the age of five. The tumor can be in only one eye or in both eyes. Retinoblastoma is usually confined to the eye and does not spread to nearby tissues or other parts of the body. 144535.doc •76- 201023852 The method provided herein can provide beneficial effects to ocular retinoblastoma patients by administering catechol butane or administering catechol butyl ketone with one or more anticancer therapies. . Eye cancer, intraocular melanoma In another aspect, a method of treating intraocular (ocular) melanoma is provided herein. Intraocular melanoma (a rare cancer) is a disease in which cancer cells are present in the eye as part of the uvea. The uvea includes the iris, ciliary body, and choroid. Intraocular melanoma most often occurs in middle-aged people. The methods provided herein can provide a beneficial effect to intraocular melanoma patients by administering catechol butane or administering catechol butane with one or more anti-cancer therapies. Endometrial Cancer In another aspect, a method of treating endometrial cancer is provided herein. Endometrial cancer is a cancer that begins in the endometrium (the inner layer of the uterus). Some examples of uterine and endometrial cancer include, but are not limited to, adenocarcinoma, acanthosis, adenosquamous carcinoma, papillary serous adenocarcinoma, clear cell adenocarcinoma, uterine sarcoma, stromal sarcoma, malignant mixed mesodermal tumor And leiomyosarcoma. The methods provided herein can provide a beneficial effect to endometrial cancer patients by administering catechol butane or administering catechol butane with - or a combination of various anti-cancer therapies. Liver Cancer In another aspect, a method of treating primary liver cancer (a cancer that begins in the liver) is provided herein. Primary liver cancer can occur in adults and children. The method provided in this article can be used by administering catechins or catechins with catechu tea. 144535.doc -77· 201023852 Butane and one. Or a combination of anti-cancer therapies to provide benefits to patients with liver cancer. This article provides a method for treating kidney cancer. Kidney cancer (also known as renal cell carcinoma or renal adenocarcinoma) is a disease in which malignant cells are present in the kidney. 1 Adding the method proposed in this article can provide favorable treatment for thyroid cancer in patients with renal cancer by administering catechins or catechins, or combination of anti-cancer therapies. This article provides methods for treating thyroid cancer. Thyroid cancer is a disease in which cancer (malignant) cells are present in thyroid tissue. The four main types of squamous cell carcinoma are papillary, follicular, and proliferative and degenerative squamous adenocarcinoma. The methods provided herein can provide a beneficial effect to thyroid cancer patients by administering catechol butane or administering catechol butane with one or more anti-cancer therapies. AIDS-related cancers Provided herein are methods of treating AIDS-related cancers including, but not limited to, AIDS-related lymphomas and Kaposi's sarcoma. The methods provided herein can provide a beneficial effect to AIDS-related cancer by administering catechol butane or administering catechol butane with one or more anti-cancer therapies. AIDS-associated lymphoma In another aspect, the present invention provides a method for treating AIDS-associated lymphoma 144535.doc • 78 · 201023852 Method. AIDS-associated lymphoma is a disease in which malignant cells are formed in the lymphatic system of patients with acquired immunodeficiency syndrome (AIDS). AIDS is caused by the human immunodeficiency virus (HIV), which attacks and weakens the body's immune system. The immune system is then unable to fight infections and diseases that affect the body. Humans with HI V disease have an increased risk of developing infections, lymphomas, and other types of cancer. Lymphoma is a cancer that affects white blood cells in the lymphatic system. Lymphoma is divided into two general types: Hodgkin's lymphoma and non-Hodgkin's lymphoma. Hodgkin's lymphoma and non-Hodgkin's lymphoma can occur in patients with aids' but not Hodgkin Lymphoma is more common. If an individual with aids has a non-Hodgkin's lymphoma, it is called an AIDs-associated lymphoma. Non-Hodgkin's lymphoma can be inert (slow growth) or invasive (rapid growth). AIDS-related lymphomas are usually invasive. The three main types of AIDS-related lymphoma are diffuse large B-cell lymphoma, b-cell immunoblastic lymphoma, and small non-cleaved cell lymphoma. The treatment of aids-associated lymphoma combines the treatment of lymphoma with the treatment of AIDS. Patients with AIDS have a weakened immune system and treatment may cause further damage. For this reason, patients with AIDS-related lymphomas are generally treated with drugs at a lower dose than patients with lymphoma who do not have AIDS. Use of anti-retroviral therapy (HA ART) to slow the progression of HIV. Drugs that prevent and treat potentially serious infections are also used. Kaposi's sarcoma In another aspect, a method of treating Kaposi's sarcoma is provided herein. Kaposi's sarcoma is a disease in which cancer cells are present in the skin or in the tissues under the mucosa of the mouth, nose and anus. Typical Kaposi's sarcoma usually occurs in Jewish, 144535.doc •79-201023852 in older men in Italy or the Mediterranean. This type of Kaposi's sarcoma develops slowly, sometimes from 1 () to 15 years. Kaposi's sarcoma can occur in humans taking immunosuppressants. Kaposi's sarcoma in patients with acquired immunodeficiency syndrome (Aids) is called epidemic Kaposi's sarcoma. Kaposi's sarcoma in people with AIDS usually spreads faster than other types of Kaposi's sarcoma and is usually present in many parts of the body. The methods provided herein can provide a beneficial effect to Kaposi's sarcoma by administering catechol butane or administering catechol butane with or in combination with an anti-cancer therapy. Virus-Induced Cancer In another aspect, provided herein are methods of treating a virus-induced cancer. Several common viruses are a clear or probable cause of the cause of a particular malignant condition. These viruses usually cause latent infections or a small number of viruses may become persistent infections. Tumor development may be associated with increased viral activation in infected hosts, and increased viral activation reflects heavy viral dose or impaired immune control. Major viral malignant disorders include hepatitis B virus (HBV) and hepatitis C virus (HCV). And hepatocellular carcinoma; type 1 human lymphotropic virus (HTLV-1) and adult tau cell leukemia/lymphoma; and human papillomavirus (HPV) and cervical cancer. In general, these malignant conditions occur at an early stage of life, usually reaching peak-values before middle or middle age. Viral-induced hepatocellular carcinoma The causal relationship between HBV and HCV and hepatocellular carcinoma or liver cancer is established by substantial epidemiological evidence. Both seem to function by chronic replication in the liver by causing cell death and subsequent regeneration. 144535.doc -80- 201023852 Virus-induced adult cell leukemia 丨 lymphoma The association between HTLV-1 and adult T-cell leukemia (ATL) has been established. Unlike other oncogenic viruses found throughout the world, HTLV-1 is highly geographically restricted' mainly found in southern Sakamoto, Caribbean, non-Western and Central, and South Pacific islands. Evidence for causality includes a single integrated viral genome in all ATL case carriers. Risk factors for HTLV-1 related malignancies appear to be perinatal infections, high viral load, and presence of male characteristics. Adult D-cell leukemia is a cancer of the blood and bone marrow. Viral-induced cervical cancer Cervical infections Human papillomavirus (HPV) is the most common cause of cervical cancer. However, not all women with HPV infection develop cervical cancer. Cervical cancer usually develops slowly over time. In the shovel of cancer in the cervix, cervical cells undergo a change called dysplasia, in which abnormal cells begin to appear in the cervical tissue. Subsequently, the cancer cells begin to grow and diffuse deeper into the cervix and surrounding areas. The methods provided herein can provide a beneficial effect to virus-induced cancer by administering catechol butane or administering catechol butane with one or more anti-cancer therapies. 'Central Nervous System (CNS) Cancer Brain and spinal forge tumors are abnormal growth of tissues present in the skull or bone spine, which is the main component of the middle (four) (four) system (CNS). Benign tumors are non-cancerous and malignant tumors are cancerous. The CNS is located in the b〇ny quarter (ie, the skull and spine), so any difference in benign or malignant 144535.doc -81 - 201023852 often causes stress on the sensitive tissue and impairs function. A tumor produced in the brain or ridge is called a primary tumor. Most primary tumors are caused by uncontrolled growth of cells surrounding and supporting neurons. In a small number of individuals, primary tumors may be caused by a specific genetic disease (such as multiple neurofibroma, tuberous sclerosis) or exposure to radiation or carcinogenic chemicals. The cause of most primary tumors remains unknown. The first test to diagnose brain and spinal tumors is a neurological examination. Special imaging techniques (computed tomography and magnetic resonance imaging, positron emission tomography) were also used to test including EEG and spinal taps. Lu biopsy (surgical procedures for suspected tumor-collecting tissue samples) helps physicians diagnose tumor types. Tumor lines are classified according to the type of cells that appear to produce tumors. The most common form of adult brain tumors comes from cells called astrocytes in the brain that make up the blood-brain barrier and contribute to the nutrition of the central nervous system. These tumors are called gliomas (astrocytoma, degenerative astrocytoma or pleomorphic glioblastoma) and account for 65% of all primary central nervous system tumors. Some tumors are (but are not limited to) oligodendroglioma, ependymoma, meningiomas, lymphomas, schwannomas, and neuroblastomas. CNS neuroepithelial tumor astrocytic tumors, such as astrocytoma; degenerative (malignant) astrocytoma such as hemisphere degenerative astrocytoma, metaneoplastic astrocytoma, degenerative astrocytoma, Brain stem degenerative astrocytoma, cerebellar degenerative astrocytoma; pleomorphic glioblastoma; hairy astrocytoma such as hemisphere hairy astrocytoma, mesencephalic astrocytoma, 144535.doc -82. 201023852 Brain stem hairy astrocytoma, cerebellum hairy star

Oral astrocytoma cell tumor; subependymal cell tumor. Oligomeric 妯 glial glioma, such as ganglioneuroma; cerebellar dysplastic ganglioneuroma (Lhermitte-Duclos); ganglion glioblastoma; degenerative (malignant) ganglion Cell tumor; profibrotic infantile ganglion glioblastoma, such as fibroproliferative infantile astrocytoma; central neurocytoma; embryonic dysplastic neuroepithelial neoplasm; olfactory neuroblastoma (esthesioneuroblastoma) ). Substantial tumors of the pineal gland, such as pineal cell tumors; pineal blastoma; and mixed pineal cell tumor/ pineal blastoma. Tumor (embryonic tumor) having neurotrophic or glial cell components, such as myeloma; primary neuroectodermal tumor with multi-directional differentiation, such as neuroblastoma; brain primitive neuroectodermal tumor; neuromuscular Cell tumor; retinoblastoma; and ependymioblastoma. Other CNS tumors 144535.doc -83- 201023852 Tumors of the Sellar Region, such as pituitary adenomas; pituitary cancer; and craniopharyngioma. Hematopoietic tumors, such as primary malignant lymphoma; plasmacytoma, and granulocyte sarcoma. Germ cell tumors, such as embryonic tissue tumors; embryonic carcinoma; yolk sac tumors (endodermal sinus tumors); choriocarcinoma; teratomas; and mixed germ cell tumors. Meningeal tumors, such as meningiomas; atypical meningiomas&apos; and degenerative (malignant) meningiomas. Non-mening epithelial tumor of the meninges (Ν〇η·menigothelial tumor) 'such as benign mesenchymal non-mesis epithelial tumors' malignant mesenchymal non-mesis epithelial tumors; primary melanocyte lesions, hematopoietic neoplasms; and uncertain tissues The resulting tumor, such as a hemangioblastoma (capillary hemangioblastoma). Cranial and spinal nerve tumors, such as the god, left sac tumor (schwannoma, neurinoma, neurilemoma); neurofibromatosis; malignant peripheral nerve sheath tumor (malignant schwannomas), such as epithelioid malignant peripheral nerve sheath tumor, divergent mesenchymal ( Divergent mesenchymal) or epithelial differentiation of malignant peripheral nerve sheath tumors and melanoma malignant peripheral nerve sheath tumors. Local spread of regional tumors; such as paraneoplastic tumors (sacralized tumors), chordoma; chonroma; chondrosarcoma; and carcinoma. Metastatic tumors 'unclassified tumors and cysts and tumor-like lesions' such as Rathke cleft cysts; epidermoid tumors; skin-like tumors, colloidal cysts in the third ventricle; intestinal cysts; The glial sac passes through 'granulocyte tumors (bulb buds, pituitary cell tumors); lower vertebral neurons hamartoma; nasal glial ectopic; and plasma cell granuloma. The methods provided herein can provide a beneficial effect to CNS tumors by administering catechol butane or administering catechol Dingxue in combination with one or more anti-cancer therapies. 144535.doc -84· 201023852 Peripheral Nervous System Cancer The peripheral nervous system consists of nerves that are separated from the brain and spinal cord. These nerves form a transmission network between the CNS and the body part. The peripheral nervous system is further divided into the body stem nervous system and the autonomic nervous system. The body stem nervous system consists of nerves leading to the skin and muscles and participates in consciousness activities. The autonomic nervous system is composed of nerves that connect the CNS to internal organs such as the heart, stomach, and intestines. It mediates unconscious activities. An acoustic neuroma is a benign fibrous growth produced by a balanced nerve (also known as the eighth cranial nerve or auditory nerve). These tumors are non-malignant tumors, meaning they do not spread or metastasize to other parts of the body. These tumors are located deep inside the skull adjacent to the important brain center of the brainstem. As the tumor enlarges, it involves surrounding structures associated with important functions. In most cases, these tumors grow slowly over several years. Malignant peripheral nerve sheath tumors (MPNST) are malignant counterparts of benign soft tissue tumors such as neurofibromas and schwannomas. It is most commonly found in soft tissue woven ice, usually very close to the nerve trunk. The most common sites include the ischial nerve, the brachial plexus, and the sarcal plexus. The most common symptom is pain, which usually requires a biopsy. It is a rare, invasive and lethal eye tumor that usually appears from the adult three-and-one nerve. Malignant PNS tumors spread along the nerve to the brain, and most patients die within 5 years of clinical diagnosis. MPNST can be divided into three main categories based on epithelial, mesenchymal or glandular features. Some MPNST include, but are limited to, subcutaneous malignant epithelioid schwannomas associated with cartilage differentiation, malignant malignant schwannomas, malignant peripheral nerve tumors with differentiation of the perineurium, and cutaneous mesoderm-like malignant nerves with rod-like features 144535.doc -85- 201023852 Tumor, superficial epithelial-like MPNST, Triton Tumor (MPNST with rhabdomyoblast differentiation), schwannomas with rhabdomyoblast differentiation. Rare cases of MPNST contain a variety of sarcoma tissue types, particularly osteosarcoma, chondrosarcoma, and angiosarcoma. It is sometimes indistinguishable from malignant mesenchymal tumors of soft tissue. Other types of PNS cancer include, but are not limited to, malignant fibrous cell tumors, malignant fibrous histiocytoma, malignant meningioma, malignant mesothelioma, and malignant mixed Miillerian tumors. The methods provided herein can provide a beneficial effect to PNS cancer by administering catechol butane or administering catechins in combination with one or more anti-cancer therapies. Oral and Oropharyngeal Cancer Controlling patients with central nervous system (CNS) cancer remains a daunting task. Cancers such as the following can be treated with the compounds described herein: squamous cell carcinoma, laryngeal cancer, nasopharyngeal cancer, oropharyngeal cancer. The methods provided herein can provide a beneficial effect on oral and oropharyngeal cancer by administering catechol butane or administering catechin butane in combination with one or more anti-cancer therapies. Gastric cancer Gastric cancer is the result of changes in the gastric lining cells. There are three major types of gastric cancer, lymphoma, gastric stromal tumors, and carcinoid tumors. Lymphoma is a cancer of the immune system that is sometimes present in the stomach wall. Gastric stromal tumors produce tissue-like tumors from the stomach wall tissue as tumors of hormone-producing cells in the stomach. The cause of stomach cancer is still controversial. The combination of genetics and environment (diet, smoking, etc.) is considered to play a part in the role of 144535.doc -86- 201023852. The methods provided herein can provide a beneficial effect to gastric cancer by administering catechol butane or administering catechol Dingxue in combination with one or more anti-cancer therapies. Testosterone

Testicular cancer is a cancer that usually occurs in one or both testes of a young male. Testicular cancer is produced in specific cells called germ cells. The two main types of germ cell tumors (GCT) in men are seminoma (60%) and non-seminoma (4%). Tumors can also be produced in the testis support and in the tissue or matrix from which the hormone is produced. These tumors are called gonadal stromal tumors. The two main types are Leydig cell tumor and Sertoli cell tumor. A secondary testicular tumor is a testicular tumor that begins in another organ and then spreads to the testis. Lymphoma is the most common secondary testicular cancer. The methods provided herein can provide a beneficial effect on testicular cancer by administering catechol butane or administering catechol butane with one or more anti-cancer therapies. Thymic cancer The thymus is a small organ located above/front of the chest that extends from the base of the throat to the front of the heart. The thymus contains two major cell types: thymic epithelial cells and lymphocytes. Thymic epithelial cells produce thymoma and thymic carcinoma. Lymphocytes in the thymus or lymph nodes can become malignant and develop into cancers called Hodgkin disease and non-Hodgkin's lymphoma. The thymus also contains another very uncommon cell type, called Kulchitsky cells or neuroendocrine cells, which usually release specific hormones. Such cells can produce a cancer called carcinoid or carcinoid (earein〇id 144535.doc -87·201023852 tumor), which usually releases the same type of hormone and is similar to other neuroendocrines from other parts of the body. A tumor produced by a cell. The methods provided herein can provide a beneficial effect on thymic cancer by administering catechol butane or administering catechin butane in combination with one or more anti-cancer therapies. Provided herein are methods of treating a skin condition comprising administering an effective amount of a pharmaceutical compound capable of inhibiting the activity of tyrosine kinase of IGF-1R and EGFR, wherein the pharmaceutical compound is catechol butane. In one aspect, the skin condition is, for example, a tumor, actinic keratosis, acne, psoriasis, skin wounds, sputum, bacterial infection, fungal infection or viral infection. Viral infections include, but are not limited to, HI V infection, HP V infection, and HSV infection. Tumors include, but are not limited to, basal eell carcinomas, squamous cell carcinoma, melanoma, hyperplastic cutaneous fibrosarcoma, Merkel cell carcinoma, and Kaposi's sarcoma. Colon and colorectal cancer Colorectal cancer (also known as colon or colorectal cancer) includes cancerous growth in the colon, rectum, and appendix. Among the 655,000 deaths per year worldwide, it is the second most common form of cancer and the second leading cause of cancer-related deaths in the Western world. Many colorectal cancers are caused by colonic adenomatous polyps. These mushroom-like growths are usually benign, but some may develop into cancer over time. In another embodiment, colorectal cancer can be classified based on the D-A classification based on the Duke classification. Stage a refers to colorectal cancer that is confined to the mucosa (ie, has not yet penetrated the intestinal wall). The 81st phase refers to the spread to the muscularis propria but does not penetrate the muscularis propria (ie, has not yet invaded the lymph nodes); 144535.doc -88- 201023852 and the B2 cancer has penetrated the muscularis propria but does not penetrate Muscle layer (ie, not yet invading the lymph nodes). First. Period refers to cancer that spreads to the muscularis propria but does not penetrate the muscularis propria (ie, involves lymph nodes); and phase C2 refers to cancer that spreads to the muscularis propria and penetrates the muscularis propria (ie, involves lymph nodes). Stage D refers to the distal metastatic spread of the β TNM system and can also be used to classify colorectal cancer according to conventional methods known in the art. The methods provided herein can be administered by administering catechol butane or administering Catechol

The combination of diced and/or multiple anticancer therapies provides a beneficial effect on colorectal cancer. The administering physician or veterinarian can readily determine and specify the "effective amount" (ED50) required for the composition to inhibit the kanji-1R. For example, the physician or veterinarian can begin with the composition used in the composition below the level required to achieve the desired therapeutic effect, and gradually increase the dosage until the desired effect is achieved. A "therapeutically effective amount" as used herein is an amount that achieves at least a portion of the desired therapeutic or prophylactic effect in an organ or tissue. In the example, the amount of inhibitor prophylaxis and/or therapeutic treatment of the disease itself is not fixed. The amount of inhibitor administered should vary with the type of disease, the extent of the disease, and the size of the mammal in question. An embodiment encompasses the use of a composition as described herein to prepare a medicament for the treatment of a condition, disease or condition as described herein. The drug may be formulated based on the need to treat 'stringer/individual physical characteristics' and may be based on the condition, disease or disease: the segment is formulated as a single- or multi-dose. The drug may be packaged in a suitable package: in a suitable package for distribution to hospitals and clinics, where the label is used: 144535.doc • 89- 201023852 Individuals suffering from the diseases described herein. The drug can be packaged in a single unit or in multiple units. As described elsewhere herein, the package may include instructions regarding the dosage of the composition and the administration of the composition. The pharmaceutical composition of the embodiments of the present invention may be formulated for administration by any administration route, such as intranasal administration; oral administration; inhalation administration; subcutaneous administration; transdermal administration; intra-arterial administration, with or without occlusion Intracranial administration; intra-dosing; intravenous administration; intra- buccal administration; intraperitoneal administration; intraocular administration; intramuscular administration; implant administration; and central venous administration. In one embodiment, catechol butane is formulated for oral administration. In another embodiment, catechol butane is formulated for intravenous administration. The catechol butane may be from about 5 mg/kg to about 375 mg/kg per dose; from about 5 mg/kg to about 250 mg/kg per dose; from about 5 mg/kg to about 200 mg/kg per dose; From about 5 mg/kg to about 150 mg/kg; from about 5 mg/kg to about 100 mg/kg per dose; from about 5 mg/kg to about 75 mg/kg per dose; or from about 5 mg/kg to about every dose A dose of 50 mg/kg is administered. Alternatively, the catechin can be administered from about 1,500 mg per day to about 2,500 mg per day; from about 1,800 mg per day to about 2,300 mg per week; or about 2,000 mg per dose in a uniform dose. In one embodiment, the catechol butane can be contacted with the target cells at a concentration ranging from about 1 μΜ to about 30 μΜ. In another embodiment, the catechol butane can be contacted with the target cells at a concentration ranging from about 1 μΜ to about 10 μΜ. In another embodiment, the NDGA can be administered at different dosing and dosing schedules, such as: (1) Oral administration twice daily at Day 1 - Day 28. Repeat treatment every 28 days without disease progression or unacceptable toxicity; 144535.doc •90- 201023852 Ο

(2) 2000 mg per oral administration; (3) Intravenous administration of the first 曰-第 曰 ' ' repeated treatment every 28 days in the absence of disease progression or unacceptable toxicity; (4) The dose was increased to a target of 汕mg per cubic centimeter of tumor volume, and subsequently, the progress of the new patient group was extended to 4 weeks per week. In the case of putative tolerance, 'continue to increase the dose so that the group can be treated for 6 weeks' and finally 8 weeks; (5) intravenously administered 24 hours a week, the dose is 100 mg / hour (24 hours 2400 mg) Beginning in 5 groups of 3 to 6 patients in increments of 25 mg per hour to a maximum of 2 mg/hr (24 hours 4800 mg) or until the maximum tolerated dose (MTD) is determined; 6) Topical application to the cervix; and (7) Increasing the dose, wherein 5 consecutive infusions were intravenously infused every 28 days. In one embodiment, the pharmaceutical composition can be administered more than once per 6 days for a period of time, or once every 2 days for a period of time. In one embodiment, the pharmaceutical composition is administered daily for four weeks. In another embodiment, each time the drug composition was again in three weeks for three weeks, and the middle cycle was started at the beginning of the cycle. In another embodiment, the pharmaceutical composition is administered daily for up to a week and then interrupted for one week. In another embodiment, the pharmaceutical composition is administered daily for two weeks, followed by two weeks of interruption. In another embodiment, the pharmaceutical composition is administered once or twice a day, or one week prior to the start of a new cycle. In another embodiment, the pharmaceutical composition is administered weekly or twice a week or twice a week. We should be aware that patients may be assessed and treated as needed, as needed, when considering the treatment cycle. . In each of the f examples, &amp; tea can be prepared by free test or its pharmaceutically acceptable salt, solvate 'polymorph, ester, tautomer or prodrug 144535.doc 201023852 . Pharmaceutical compositions comprising catechol butane or a pharmaceutically acceptable &lt;salt, solvate, polymorph, ester, tautomer or prodrug thereof are also described. The compounds and compositions described herein can be administered as a pharmaceutical composition, either alone or in combination with a pharmaceutically acceptable carrier, excipient or diluent, according to standard pharmaceutical practice. In addition to the above examples and examples of administration, circulation, and circulation schedule, the above-described various changes in the administration, circulation, and cycle schedules for co-administered compounds and second chemotherapeutic compounds, radiation therapy, or surgery are encompassed herein. It can be administered as determined by a qualified medical professional based on the patient, type of cancer, and/or appropriate when the treatment progresses. In various embodiments, the therapeutically effective amount of the catechol butane dose described herein is used. In various embodiments, catechol butane is administered to minimize toxicity to the patient. In some embodiments, catechol butane is administered in a manner suitable for providing specific pharmacokinetic (pk) parameters in a human patient. In some embodiments, catechol butane is administered in a manner suitable for providing a specific maximum blood concentration (cmax) of catechol butane. In some embodiments, the butane is administered in a manner suitable for providing a maximum blood concentration for the known catechol butane (in some embodiments, to provide a pupa The area under the specific plasma concentration curve (AUC) of the alkane is given to the catechins. In some embodiments, to provide a specific clearance rate (CL/F) or specific half-life of the catechin (Τι/) 2) The manner in which catechin is given to catechins Unless otherwise specified, the ΡΚ parameters described herein (including the scope of the accompanying claims) refer to H4535.doc • 92 for at least 3 patients at the same dosing schedule. · 201023852 Average PK value for the group. Therefore 'unless otherwise specified: auc = average AUC for groups of at least 3 patients; Cmax = average Cmax for groups of at least 3 patients, Tmax = at least 3 patients Average of the groups; τ,,, = average τ1/2 of the group of at least 3 patients; and CL/F = group of at least 3 patients. Average CL/F of the group. In some embodiments, average Value is at least 6 patients • or at least 12 patients or at least 24 patients or at least 36 patients The average of the group. If it is a non-average PK value, it will indicate that the value is only relevant to the individual. Likewise, unless otherwise stated, AUC refers to the average AUC of a group of at least 3® patients, Infinite extrapolation according to the standard clearing model. If you want the AUC for a specific time, you should specify the start (X) and end (y) time of the "Auc" by the suffix name (for example, AUCx, y). One aspect of the embodiments provides a method of treating cancer using a combination of different treatment regimens. For example, the catechol butane compounds and one or more of various anti-neoplastic chemotherapeutic agents, chemopreventive agents, side effects limiting agents And/or anti-neoplastic therapy (eg, surgery) combination. In any of the methods provided herein, the individual may additionally administer one or more additional anti-cancer agents. As noted above, such other cancer therapies may be, for example, surgery , radiation therapy, administration of a chemotherapeutic agent, and any combination of these methods. Combination therapy may be performed sequentially or simultaneously, and the combination therapy may be neoadjuvant therapy or adjuvant therapy. Agents include, but are not limited to, DNa breakers, topoisomerase inhibitors, and mitotic inhibitors. Many chemical and therapeutic agents are currently known in the art and can be used with the compounds described herein: Use. In some embodiments The chemotherapeutic agent is selected from the group consisting of 144535.doc • 93· 201023852 group: mitotic inhibitors, alkylating agents, antimetabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, Enzymes, topoisomerase inhibitors, biological response modifiers, anti-hormones, angiogenesis inhibitors and antiandrogens. In one embodiment, the individual to be treated may be resistant to treatment with at least one tyrosinase inhibitor (e.g., only an EGFR inhibitor, only an IGF_1R inhibitor inhibitor and an IGF-1R inhibitor). The terms "cancer treatment", "cancer therapy" and the like as used herein encompass the following treatments, such as surgery (such as cutting, resection, ablation (by physical or chemical means or a combination of physical or chemical methods), suturing a laser Processing or otherwise physically altering body tissues and organs), radiation therapy, administration of a chemotherapeutic agent, and any combination or combination of these methods. Combination therapies can be performed sequentially or simultaneously. Treatments such as radiation therapy and/or chemotherapy that are administered prior to surgery are referred to as neoadjuvant therapy. Treatments administered after surgery, such as radiotherapy and/or chemotherapy, are referred to herein as adjuvant therapies. Examples of procedures that can be used in cancer treatment include, but are not limited to, eradication prostatectomy, cryotherapy, mastectomy, breast tumor resection, transurethral resection of the prostate, and the like. Many chemotherapeutic agents are known and act through a variety of modes of action. In some non-limiting embodiments, the chemotherapeutic agent is a cytotoxic agent, an anti-proliferative agent, a targeting agent (such as a kinase inhibitor and a cell cycle regulator), or a biological agent (such as a cytokine, vaccine, viral agent, and other immune agents). The nature of the stimulant, such as BCG, hormones, monoclonal antibodies, and siRNA^, in combination therapy with a chemotherapeutic agent, depends on the type of agent used. 144535.doc -94- 201023852 If combination therapy is covered, then 丨 丨Inhibitors are not intended to be limited by the particular nature of the combination. For example, 'inhibitors can be administered in combination as a simple mixture as well as in a chemically hybrid (hybrld) form - examples are compounds covalently linked to a dry carrier or active drug. The valence combination can be achieved in a variety of ways, such as, but not limited to, the use of commercially available cross-linking compounds. As used herein, the terms "pharmaceutical combination", "administering another therapy", "administering another therapeutic agent", and A similar term refers to a pharmaceutical therapy produced by mixing or combining more than one active ingredient, and includes both fixed and non-fixed combinations of active ingredients. "Fixed combination" means that the inhibitor is administered to the patient simultaneously with at least one adjuvant in a single entity or agent (IV). The term "non-fixed combination" means variable insertion into the patient simultaneously, collectively or sequentially in the form of a separate entity. The time limit administration inhibitor and at least one adjuvant, wherein the administration provides an effective amount of the two or more compounds in the patient. It is also suitable for combination therapy, for example, administration of three or more active ingredients. The terms "co-administered", "combined with", and grammatically equivalent terms or the like, as used herein, are intended to encompass the administration of a selected therapeutic agent to a single patient, and are intended to include the same or different a route of administration or a treatment regimen for administering the agent at the same or different times. In some embodiments, the inhibitor ..., the drug is co-administered. These terms encompass the administration of two or more agents to the animal' So that both agents and/or their metabolites are present in the animal simultaneously, including simultaneous administration in separate compositions, administration in separate compositions at different times, and/or in both agents The composition is administered. Thus, in some embodiments, the inhibitor and other agents are administered as a single composition. In some embodiments, the 'inhibitor and other agents are mixed in the composition 144535.doc - 95-201023852. As used herein, "anticancer or anticancer therapy" means (but is not limited to) a chemotherapeutic agent, nucleic acid disrupting agent, nucleic acid disrupting therapy, anticancer antibody, antiproliferative agent or antibiotic used in an individual. Proliferative Therapy. It is to be understood that the following list of treatment regimens represents conventional therapies, but the present invention encompasses other known therapeutic regimens not specifically disclosed herein. Suitable anti-neoplastic chemotherapeutic agents to be used in the methods of the invention include (but Not limited to) alkylating agents, antimetabolites, natural antibiotics, hormonal antibiotics, angiogenesis inhibitors, differentiation agents, RNA inhibitors, antibodies or immunotherapeutics, gene therapy agents, small molecule enzyme inhibitors , biological response modifiers and anti-cancer transfer agents. Hyuning Agents Alkylating agents are known to function by alkylating macromolecules, such as DNA of cancer cells, and are typically strong electrophiles. This activity disrupts DNA synthesis and cell division. Examples of alkylating agents suitable for use herein include nitrogen mustard and its analogs and derivatives, including cyclophosphamide, ifosfamide, chlorambucil, estramust Estramustine, mechlorethamine hydrochloride, melphalan, and uracil mustard. Other examples of stimuli include alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomustine, and streptozotocin). Streptozocin)), triazene (eg dacarbazine and temozolomide), ethyl imine/methyl melamine (eg altretamine and thiotepa) Thiotepa)) and methyl 肼 144535.doc -96- 201023852 derivatives (such as procarbazine). The burn-in group includes an alkaloid-containing drug, including carboplatin, cisplatin, and oxaliplatin. Antimetabolites Anti-metabolite anti-neoplastic agents are structurally similar to natural metabolites and are involved in cancer cells. Normal metabolic processes, such as the synthesis of nucleic acids and proteins. It is sufficiently different from natural metabolites that it can interfere with the metabolic processes of cancer cells. Suitable anti-metabolic anti-neoplastic agents to be used in the methods of the invention may be classified according to their metabolic pathways and may include, but are not limited to, folic acid, pyrimidine, purine and cytidine analogs and derivatives. . Members of the folic acid group of agents useful herein include, but are not limited to, methotrexate (amethopterin), pemetrexed, and analogs and derivatives thereof. Pyrimidine agents suitable for use herein include, but are not limited to, cytarabine, floxuridine, fluorouracil (5-fluoropurine shouting), capecitabine (capecitabine) , gemcitabine and its analogues and derivatives. Suitable 本文 呤 呤 适用 包括 包括 包括 包括 包括 包括 包括 包括 包括 包括 包括 包括 包括 包括 包括 包括 包括 包括 包括 包括 包括 包括 包括 包括 包括 包括 包括 包括 包括 包括 包括 包括 包括 包括 包括 包括 mer mer mer mer mer mer mer mer mer mer mer mer mer mer mer mer Cladribine and its analogues and derivatives. Suitable cytidine agents for use herein include, but are not limited to, cytarabine (cytosine arabinoside), azacitidine (5-azacytidine), and analogs and derivatives thereof. . Natural anti-biological agents Natural anti-neoplastic agents include anti-mitotic agents, biotin antibiotics, hi 144535.doc -97- 201023852 camptothecin analogs and enzymes. Anti-mitotic agents suitable for use herein include, but are not limited to, vinca alkaloids, such as vinblastine, vincristine, vindesine, vinorelbine. And their analogues and derivatives. It is derived from the plant of Madagascar peri winkle and usually has cell cycle specificity for the μ phase and binds to tubulin in the microtubules of cancer cells. Other anti-mitotic agents suitable for use herein are podophyllotoxin&apos; which include, but are not limited to, etoposide, teniposide, and analogs and derivatives thereof. ❹ These agents are primarily targeted at the G2 and S stages of the cell cycle. Natural antibiotics also include antibiotic antibiotics. Antibiotic antibiotics are antibacterial agents that have antitumor properties, usually through interaction with cancer cell DNA. Antibiotic antibiotic agents suitable for use herein include, but are not limited to, belomycin, dactinomycin, doxorubicin, idarubicin, epirubicin ( Epirubicin), mitomycin, mitoxantrone, pentastatin, plicamycin, and analogs and derivatives thereof. Natural antibiotic biocide classifications also include camptothecin analogs and derivatives suitable for use herein, and include Xishu, Topotecan and Irinotecan (mnotecan). These agents act primarily by targeting the cellular ribozyme topoisomerase 1. Another subclass of natural antibiotic agents is the enzyme L-aspartate and its variants. L-aspartate indoleamine is used as a 144535.doc -98· 201023852 by catalyzing the hydrolysis of aspartic acid and ammonia to the aspartate and ammonia to remove some of the cancer cells. Hormone antibiotics Hormone antibiotics mainly play a role in hormone-dependent cancers and cells related to prostate tissue, breast tissue, endometrial tissue, ovarian tissue, lymphoma and leukemia. Such tissues may respond to classes of agents such as glucocorticoids, progesterone, estrogens, hormones and androgens and will depend on the class of such agents. Both analogs and derivatives as agonists or antagonists are suitable for the treatment of tumors. Examples of glucocorticoid agonists/antagonists suitable for use herein are beta dexamethasone, cortisol, corticosterone, prednisone, and mifepristone I ( Mifepristone) (RU486), analogs and derivatives thereof. Suitable progesterone agonist/antagonist sub-agents for use herein include, but are not limited to, hydroxyprogesterone, medroxyprogesterone, megestrol acetate, mifepristone (RU486), ZK98299, analogs and derivatives thereof. Examples of estrogen agonist/antagonist subclassing agents suitable for use herein include, but are not limited to, estrogen, tamoxifen, toremifene, RU58668, SR16234, ZD164384, ZK191703, Fulvestrant, its analogues and derivatives. Examples of aromatase inhibitors suitable for inhibiting estrogen production herein include, but are not limited to, androstenedione, formestane, exemestane, aminoglutethimide ), anastrozole, letrozole, analogs and derivatives thereof. Examples of androgen agonist/antagonist subclassing agents suitable for use herein include (but 144535.doc -99-201023852 is not limited to) testosterone, dihydrotestosterone, fluoxymesterone, Testolactone, decyl ketone, testosterone propionate, gonadotropin-releasing hormone agonist/antagonist (eg leuprolide, goserelin, triptorelin) ), buserelin, diethylstilbestrol 'abarelix, cyproterone, flutamide, nilutamide, bicel Bicalutamide, its analogues and derivatives. Angiogenesis inhibitors ❹ Angiogenesis inhibitors act by inhibiting angiogenesis in tumors. The angiogenesis inhibitors encompass a variety of agents, including small molecule agents, antibody agents, and agents that target RNA function. Examples of angiogenesis inhibitors suitable for use herein include, but are not limited to, ranibizumab, bevacizumab, SU11248, PTK787, ZK222584, CEP-7055, angiozyme, and Heparin (dalteparin), thalidomide, suramin, CC-5013, combretatin A (combretastatin) A4 sate, LY317615, soy isoflavone, AE-941, interference α, PTK787/ZK 222584, ZD6474, EMD 121974, ZD6474, BAY 543-9006, celecoxib, halofiginone hydrobromide, bevacizumab, analogues thereof, variation Body or derivative. Differentiation Agents Differentiators inhibit tumor growth via a mechanism that induces differentiation of cancer cells. One such subclass of agents suitable for use herein includes, but is not limited to, vitamin A analogs 144535.doc -100- 201023852

❹ or retinoid and peroxisome proliferator-activated receptor agonist (PPAR). Retinoids suitable for use herein include, but are not limited to, vitamin A, vitamin A aldehyde (retinal), retinoic acid, fenretinide, 9-cis- Retinoids, 13-cis-retinoids, all-trans-retinoic acid, isotretinoin, tretinoin, retinyl palmitate, analogs and derivatives thereof. Affiliating agents for PPAR suitable for use herein include, but are not limited to, troglitazone, ciglitazone, tesaglitazar, analogs and derivatives thereof. RNA Inhibitors Specific RNA inhibitors can be used to inhibit the expression or translation of messenger RNA ("mRNA") associated with a cancer phenotype. Examples of such agents suitable for use herein include, but are not limited to, short interfering RNA ("siRNA"), ribonuclease, and antisense oligonucleotides. Specific examples of RNA inhibitors suitable for use herein include, but are not limited to, Cand5, Sirna-027, fomivirsen, and anginase. Antibody/Immune Therapeutic Agents Antibody agents bind to targets that are selectively expressed in cancer cells and can use binding to kill cells associated with the target or trigger an immune response in the body to destroy cancer cells. The immunotherapeutic agent can be composed of a plurality of antibodies or monoclonal antibodies. The antibody may be composed of a non-human animal (e.g., mouse) and a human component, or may be composed entirely of human components ("humanized antibody"). Examples of monoclonal immunotherapeutic agents suitable for use herein include, but are not limited to, rituximab (touxibimab), tosibtumomab, and Imodan 144535.doc • 101 that target the CD-20 protein. · 201023852 Resistance (ibritumomab). Other examples suitable for use herein include trastuzumab, edrecolomab, bevacizumab, cetuximab, carcinoembryonic antigen antibody, gemtuzumab (gemtuzumab) ), alimtuzumab, mapatumumab, panitumumab, EMD 72000, TheraCIM hR3, 2C4, HGS-TR2J and HGS-ETR2. Gene Therapeutic Agents Gene therapeutic agents insert a gene copy into a specific patient cell group and target both cancer cells and non-cancer cells. The goal of gene therapy can be to replace the variable gene with a functional gene, stimulate the patient's immune response to cancer, make cancer cells more sensitive to chemotherapy, and place "suicide" genes in cancer cells or inhibit angiogenesis. The gene can be delivered to the target cell using a virus, liposome or other vector. This can be done by injecting the gene vector composition directly into the patient or by injecting it into the patient ex vivo, wherein the infected cells are reintroduced back into the patient. These compositions are suitable for use in the method of the invention. Small molecule enzyme inhibitor-specific small molecule therapeutics are capable of targeting tyrosine kinase activity of specific cellular receptors such as epidermal growth factor receptor ("EGFR") or vascular endothelial growth factor receptor ("VEGFR") or Downstream signal transduction signal. This targeting by small molecule therapeutics can produce an anti-cancer effect. Examples of such agents suitable for use herein include, but are not limited to, imatinib, gefitinib, erlotinib, lapatinib, canertinib. ZD6474, sorafenib (BAY 43-9006), ERB-569 and analogues and derivatives thereof. 144535.doc -102- 201023852 Biological Response Modulators Specific protein or small molecule agents can be used for anticancer therapy via direct anti-tumor effects or via indirect effects. Examples of direct acting agents suitable for use herein include, but are not limited to, differentiating agents (such as retinoids and retinoid derivatives). Suitable for use herein are, but are not limited to, agents that modulate or promote the immune system or other systems, such as interferons, interleukins, hematopoietic growth factors (eg, erythropoietin), and antibodies (single and polyclonal antibodies). ). Anticancer Transfer Agent The process by which cancer cells spread from the initial tumor site to other locations around the body is called cancer metastasis. Certain agents have anti-cancer transfer properties designed to inhibit the spread of cancer cells. Examples of such agents suitable for use herein include, but are not limited to, marimastat, bevacizumab, trastuzumab, rituximab, erlotinib, MMI-166, GRN163L Hunter-killer peptide, tissue inhibitor of metalloproteinase (TIMP), analogs, derivatives and variants thereof. Chemopreventive agents Certain agents can be used to prevent the initial production of cancer or to prevent recurrence or cancer metastasis. The combination of these chemopreventive agents with one or more other anticancer agents, including catechins, can act to treat cancer and prevent cancer recurrence. Examples of chemopreventive agents suitable for use herein include, but are not limited to, tamoxifen, raloxifene, tibolone, bisphosphonate, ibandronate ), estrogen receptor modulator, aromatase inhibitor (letrozole, anastrozole), jaundice hormone releasing hormone agonist, goserelin, vitamin A, retinal, retinal 144535.doc •103- 201023852 Acid, fenretinide, 9-cis-retinoic acid, 13_cis-retinoic acid all-trans-retinoic acid, isotretinoin, retinoid, vitamin B6, vitamin B12, Vitamin C, vitamin D, vitamin E, cyclooxygenase inhibitor, non-steroidal anti-inflammatory drug (NSAID), aspirin, ibuprofen, celec〇xib, polyphenols, Polyphenols £, green tea extract, folic acid, glucaric acid, interferon-α, anethole dithiolethione, rheumatism, u-bilol, finasteride , 〇沙嗤嗓 (d〇xazosin), code, 0 〇 〇-carbene (carbinal), α- Fluoroguanosine, carotenoids, carotenoids, lycopene, antioxidants, coenzyme Q1, flavonoids, quercetin, curcumin, catechins, epigallocatechin Acid ester, N-acetinyl cysteine, indole-3-carbinol, phytate, isoflavone, glucanic acid, rosemary, soybean, saw palmetto 〇) Peace Treaty. Side effect limiting agents The treatment of cancer with catechol butane alone or in combination with other anti-neoplastic compounds may be accompanied by administration of an agent which can alleviate the side effects produced by the anti-biological agent. Such agents suitable for use herein include, but are not limited to, anti-emetic agents, anti-mucosal agents, pain control agents, infection control agents, and anti-anemia/anti-thrombotic agents. Examples of anti-emetic agents suitable for use herein include, but are not limited to, serotonin 3-conformity antagonists, met〇ci〇pramide, steroids, lorazepam, angdan Examples of anti-mucosal agents suitable for use herein include, but are not limited to, paclivirin ({) &amp; 11 &amp; sinensis (cannabin), cannabinoids, analogs and derivatives thereof. 〇11111) (keratin 144535.doc 201023852 cell growth factor), glucagon peptide-2, teduglutide, L-glutamine, amifostin and fibroblast growth factor Examples of pain management agents suitable for use herein include, but are not limited to, opioids, opiates, and non-steroidal anti-inflammatory compounds. Examples of agents useful for controlling infections herein include, but are not limited to, antibacterial agents, such as aminosides, penicillins, cephalosporins, tetracyclines, linnoides Clindamycin, lincomycin, macrolide, vancomycin, carbapenem, monobactam, fluocinolone Fluoroquinolone), sulfonamide, nitrofurantoin, analogs and derivatives thereof. Examples of agents useful in the treatment of anemia or thrombocytopenia associated with chemotherapy include, but are not limited to, erythropoietin and thrombopoietin. Several other suitable therapies for use in combination with the catechol butanes and other compounds described herein can also be used. See, for example, Goodwaw ά: Public

The Pharmacological Basis of Therapeutics, 11th Edition, Brunton LL, Lazo JS and Parker KL, ed. McGraw-Hill, New York, 2006 ° Infected Cancer In one embodiment, the cancer is ovarian cancer and one or more therapeutic treatments are Surgery, chemotherapy (eg cranberries; doxil hydrochloride; gemcitabine; Rubitecan; and platinum-based chemotherapeutic agents such as cisplatin, carboplatin and acesulfide) Melphalan, Pacific paclitaxel 144535.doc •105· 201023852 (paclitaxel), topoisomerase I inhibitors (such as topotecan and irinotecan), taxane based therapy, hormones, radiation therapy , systemic hypothermia, isoflavone derivatives (such as Phenoxodial), cytotoxic macrolides (such as Epothilone), angiogenesis inhibitors (such as bevacizumab), signals Transduction inhibitors (such as trastuzumab), gene therapy, RNAi therapy, immunotherapy, monoclonal antibodies, phospholipid-based cyclohexanol kinase inhibitors (such as rapamycin) or any of them Co. In another embodiment, the therapeutic treatment is a VEGF receptor inhibitor. Non-limiting examples of VEGF receptor inhibitors include bevacizumab (AVASTIN®), ranibizumab (LUCENTIS®), VEGF-Trap, sunitinib (SUTENT®), sorafenib ( NEXAVAR®), axitinib, n. pegaptanib, and pazopanib. In one embodiment, the cancer is liver cancer, and one or more anticancer therapies are for example Surgery, immunotherapy, radiation therapy, chemotherapy, and percutaneous ethanol injection. The types of surgery that can be used are cryosurgery, partial hepatectomy, total hepatectomy, and radiofrequency ablation. Radiation therapy can be extracorporeal beam radiation therapy, proximity radiation therapy, radiosensitizers or radiolabeled antibodies. Other treatment types include hyperthermia and immunotherapy. Skin Cancer Different treatment types for patients with non-melanoma and melanoma skin cancer and actinic keratosis include surgery, radiation therapy, chemotherapy, and photodynamic therapy. Some of the possible surgical options for treating skin cancer are Mohs 144535.doc -106- 201023852, microhurgical surgery, simple resection, electro-drying and curettage, cryosurgery, and laser surgery. Radiation therapy can be extracorporeal beam radiation therapy or proximity radiation therapy. Other treatment types tested in clinical trials are biotherapy or immunotherapy, chemoimmunotherapy, topical chemotherapy with fluorouracil and photodynamic therapy. Endometrial Cancer In one embodiment, the cancer is endometrial cancer and one or more anti-cancer therapies are, for example, surgery, radiation therapy, chemotherapy, gene therapy, photodynamic therapy, anti-angiogenic therapy, and immunotherapy. Or a combination thereof. In one embodiment, the cancer is kidney cancer and one or more of the therapeutic treatments are surgery, chemotherapy, bevacizumab (AVASTIN®), ranibizumab (LUCENTIS®), VEGF-Trap, sultanate SUTENT®, Sorafenib (NEXAVAR®), axitinib, pegaptanib, pazopanib, interferon-a, IL-2 or any combination thereof. Testicular cancer In one embodiment, the cancer is testicular cancer and the one or more anti-cancer therapies are, for example, surgery, immunotherapy, chemotherapy, radiation therapy, chemotherapy, radiation therapy or combination therapy. Several drugs are commonly used to treat testicular cancer: Platinol (cisplatin), Vepesid (Vepesid) or VP-16 (etoposide) and Blenoxane (Boleoxane) Sulfate). In addition, Ifex (isocyclic phosphoniumamine), vinblastine (Velban) (vinca sulfate) and others can be used. Gastric Cancer: 144535.doc -107- 201023852 In one embodiment, the cancer is testicular cancer, and one or more anti-cancer therapies are, for example, surgery, immunotherapy, chemotherapy, radiation therapy, combination of chemotherapy and radiation therapy or biological therapy . Thymic Cancer In one embodiment, the cancer is thymic carcinoma and the one or more anti-cancer therapies are, for example, surgery, immunotherapy, chemotherapy, accidental therapy, combination of chemotherapy and radiation therapy or biological therapy. Anticancer drugs that have been used to treat thymoma and thymic cancer are cranberries (Adriamycin), cisplatin, isocyclic squamous amines, and corticosteroids (prednisone). Typically, such drugs are provided in combination to increase their effectiveness. Combinations for the treatment of thymic cancer include cisplatin, cranberry, etoposide and cyclophosphamide, and combinations of cisplatin, cranberry, cyclophosphamide and vincristine. Osteoblasts In one embodiment, the cancer is myeloma and one or more of the therapeutic treatments are surgery, radiation therapy, VELCADE®, lenalidomide or talcamine or a combination thereof. In one embodiment, the therapeutic treatment is VELCADE®. The dosage of any such therapy is known in the art and can be adjusted accordingly with the combination therapy. Prostate Cancer In the examples, the cancer is prostate cancer, and one or more therapeutic treatments are surgery, radiation therapy (eg, extracorporeal beam radiation therapy or proximity radiation therapy), hormone removal (androgen suppression), heat shock protein 9 ( Hsp9〇) Inhibitor chemotherapy (eg docetaxel; platinum-based chemotherapy, such as cisplatin, carboplatin, satraplatin, and aussie 144535.doc 201023852; yew ; female Moss lamp), prednisone or prednisolone, cholesterol-lowering drugs (such as statin), luteinizing hormone releasing hormone (LHRH) agonist, RNAi therapy, whole tumor cells Modifications are made to secrete granulocyte macrophage-community stimulating factor (GM-CSF) (also known as GVAX) or any combination thereof. In another embodiment, the one or more therapeutic treatments are . VEGF receptor inhibitors. Non-limiting examples of VEGF receptor inhibitors include bevacizumab (AVASTIN®), ranibizumab (LUCENTIS®), VEGF-Trap, sunitinib (SUTENT®), sorafenib (NEXAVAR®) , Axitininib, β-Putatani and Pa. Lung Cancer In one embodiment, the cancer is lung cancer, and one or more of the therapeutic treatments are surgery, radiation therapy (e.g., chest radiotherapy, radiotherapy using charged particles), urine. Uracil-tegafur and chemotherapeutic based (eg cisplatin, carboplatin, acesulfide, etc.) and vinorelbine, erlotinib (TARCEVA®), gefitinib (IRESSA®), anti-EGFR antibody (eg cetuximab), anti-vascular endothelial growth factor antibody (eg bevacizumab), small molecule inhibitor of tyrosine kinase, involved in lung cancer cell proliferation Direct inhibitor of protein, Aurora kinase inhibitor, laser-induced heat therapy, RNAi therapy, whole tumor cell genetic modification to secrete granulocyte macrophage-community stimulating factor (GM-CSF) (also known as ' GVAX), bevacizumab (AVASTIN®), ranibizumab (LUCENTIS®), VEGF-Trap, sunitinib (SUTENT®), sorafenib (NEXAVAR®), axitinib, pega Tani and pazopanib or any combination thereof. Another therapeutic treatment includes Taxol and Pemetrex 144535.doc-109-201023852 azole. The dosage of any such therapy is known in the art and can be adjusted accordingly with the combination therapy. Breast Cancer In one embodiment, the cancer is breast cancer and one or more therapeutic treatments are surgery, monoclonal antibodies (eg, Her-2 antibody, herceptin, bevacizumab (AVASTIN®), Lenny's single Antibiotics (LUCENTIS®), SUTENT® (SUTENT®), sorafenib (NEXAVAR®), axitinib, pegaptanib and pazopanib), adjuvant chemotherapy (such as single agent chemotherapy or Combination chemotherapy (eg, combination chemotherapy based on anthracycline- and yew-burning, paclitaxel or with or without endocrine manipulation with or without PMRT target-specific trastuzumab, Changchun Ruibin)), VEGF-Trap, xeloda, taxotere, doxorubicin, cyclosporin, Xeloda, dextrosamine, selective estrogen receptor modulator (such as Tamoxifen and raloxifene), ectopic estrogen receptor modulators (such as Trilostane), radiation (eg, interstitial proximal radiotherapy, Mammosite devices, 3-dimensional conformal radiation and Radiation therapy during surgery), aromatase inhibitors that inhibit systemic synthesis (eg A Qufu, exemestane and letrozole), RNAi therapy, rapamycin intravenous analogues with immunosuppressive and antiproliferative properties (such as Temsirolimus (CCI779)) or any combination thereof . The dosage of any such therapy is known in the art and can be adjusted accordingly with the combination therapy. In one embodiment, the cancer is colon cancer, and one or more of the therapeutic treatments are surgery, radiation therapy, and chemotherapy (eg, 5-fluorourine, seizure, left-handedness, 144535.doc-110- 201023852 (levamisole), leucovorin or semustine (thiol-CCNU), N-[2-(dimethylamino)ethyl]anthracene-4-carbamide And other related indoleamine anticancer drugs; non-topoisomerase II inhibitors, irinotecan, liposomal topotecan, taxane anticancer agents (eg • paclitaxel or docetaxel), ° Occupy ketone acetate compounds (eg, 5,6-dimethylpyrone-4-acetic acid PMAA), laminarin, site-selective cyclic AMP analogs (eg, 3', 5'-ring 8-alkaline phosphate phosphate, Cox-2 travel miso, ° inhibitor, Cox-2 squat inhibitor, Cox-2 ® tetrahydrocarbazole inhibitor, Cox-2 inhibitor, Localized inhibitor of NSAID (eg, o-amino acid, aspirin (5- acetic acid), azodisal sodium, carboheterocyclic acid, Carprofen, chlorfenapyr, diclofenac, fenbufen, fenclofenac, fenoprofen, flufenamic acid, fluoride Flurbiprofen, fluprofen, furosemide, gold sodium thiomalate, ibuprofen, indomethacin, "51 indoprofen, ketoprofen, lonazolac, loxoprofen, meclofenamic acid, mefanic acid (mefanamic Acid), melphalan, naproxen, penicillamine, phenylacetic acid, propionic acid, salicylic acid, sulfoxide, pyridine, sulindac, tolmetin , pyrazolone, butazone, propazone, NSAID, 144535.doc 201023852, meloxicam, oxicam, piroxicam, Feldene, ° biroxicon beta-cyclodextran, tenoxicam , etodolac and oxaprozin, inhibitors of HER-2/neu, RNAi therapy, GM-CSF, monoclonal antibodies (eg anti-Her-2/neu antibodies, anti-CEA antibodies, A33 (HB 8779), 100-210 (HB 11764) and 100-310 (HB 11028)), bevacizumab (AVASTIN®) 'Lanibizumab (LUCENTIS®), VEGF-Trap, sunitinib ( SUTENT®), Sorafenib (NEXAVAR®), Axitinib, Begathanib, Paputy and Erbitux, Vectibix, Hormone Therapy, Pyridine , Xishu test derivatives (such as CPT-11), road folic acid (FA), gemcitabine, Ara-C, based on chemotherapeutic agents (such as cisplatin, carbopol and acesulfide), cGMP-specific phosphoric acid Esterase inhibitor or any combination thereof. The dosage of any such therapy is known in the art and can be adjusted accordingly with the combination therapy. In one embodiment, the cancer is pancreatic cancer, and one or more therapeutic treatments are surgery, radiation therapy (RT), fluorouracil (5-FU) and RT, systemic therapy, stent placement Stenting, gemcitabine (GEMZAR®), gemcitabine and RT, cetuximab, erlotinib (TARCEVA®), chemoradiation, bevacizumab (AVASTIN®) or any combination thereof. The dosage of any such therapy is known in the art and can be adjusted accordingly with the combination therapy. Cervical Cancer In one embodiment, 'cancer is cervical cancer, and one or more anti-cancer therapies 144535.doc -112· 201023852 includes, but is not limited to, surgery, immunotherapy, and some possible surgical options are therapy and chemotherapy. Palace resection. The second of the patients with cervical cancer = de-surgery and eradication therapy or near-radiation therapy 1 including extracorporeal beam radiation, a part of the a-s-arapeutic therapy, and the anti-cancer drugs for the treatment of the cervical cancer Shun Fukang, Bolais and main sputum Platinum, hydroxyurea, irinote, _ Changchun, silk, sputum, heterocyclic amine, urinary oxime, etoposide, amidoxime and their combinations. Sickle adenocarcinoma ❿ In the embodiment, the cancer is thyroid cancer, and one or more anti-cancer therapies include G, no treatment, surgery, immunotherapy, radiation therapy, hormone therapy, and stemming therapy. Surgery is the most common treatment for squamous adenocarcinoma. Some of the possible surgical options for thyroid cancer are lobectomy, total thyroidectomy, and total thyroidectomy. Radiation therapy can be an external radiotherapy or a liquid that may require exposure to radioactive moths. Hormone therapy uses hormones to stop cancer cells from growing. In the treatment of thyroid cancer, hormones can be used to stop the body from producing other hormones that cause cancer cells to grow. EGFR inhibitor resistance and overexpression of EGFR inhibitors Epidermal growth factor receptor (EGFR) or its ligand tGFc^^ is often associated with, for example, breast cancer, lung cancer, and head and neck cancer, and it is believed to contribute to these tumors. Malignant growth. The area of intensive research work is the development of compounds that are useful as antitumor agents to inhibit EGFr kinase activity and antibodies that block EGFR activation. Epidermal growth factor (EGF), which acts via the receptor EGFR, is an epithelial mitogen and a survival factor (Rheinvvald, JG and Green, H., 144535. doc-113-201023852 1977, Nature 265, 421; Rodeck, U. Et al., 1997, J. Cell Science 110, 113). Therefore, the use of EGFR inhibitors in chemotherapy may interfere with the normal renewal of skin and other epithelial tissues, such as the inner layer of the cornea and the gastrointestinal tract: toxicity to proliferating tissues such as the skin and GI tract is usually the dose of cytotoxic agents. Restrictive side effects. This toxicity can be manifested, inter alia, as a rash, diarrhea, thinning of the cornea, loss or loss of hair, abnormal hair follicle development, degeneration, necrosis or inflammation, inability to heal or heal after prolonged epidermal growth or injury. The term "EGFR inhibitor" as used herein refers to any EGFR inhibitor currently known or later identified in the art, and includes administration to a patient such that it inhibits biological activity associated with EGFR activation in the patient (including Any entity that otherwise has any downstream biological effects due to the binding of the natural ligand of EGFR to EGFR. Such EGFR inhibitors include any agent that blocks EGFR activation or any downstream biological effect of EGFR activation associated with treating cancer in a patient. Such an inhibitor acts by directly binding to the intracellular domain of the receptor and inhibiting its kinase activity. Alternatively, the inhibitor may act by blocking or reducing its normal biological activity by occupying a ligand binding site or a portion thereof of the EGFR receptor or a portion thereof, thereby rendering the receptor inaccessible to its natural ligand. EGFR inhibitors include, but are not limited to, low molecular weight inhibitors, antibodies or antibody fragments, antisense constructs, and ribonucleases. In a preferred embodiment, the EGFR inhibitor is an organic small molecule or an antibody that specifically binds to human EGFR. EGFR inhibitors that can be used in accordance with the methods of the invention include, but are not limited to, the EGFR inhibitors classified in the art as follows: 喧 喧 EGFR inhibition 144535.doc -114-201023852, pyridinium EGFR inhibitor, Pyrimidine pyrimidine EGFR inhibitor, ° pymidine EGFR inhibitor, "pyrazine EGFR inhibitor, phenylamino-pyrimidine EGFR inhibitor, hydroxy 吲哚 EGFR inhibitor, 丨 丨 幷咔 幷咔An azole EGFR inhibitor, a 呔嗓 EGFR inhibitor, an isoxanthin EGFR inhibitor, a quinone EGFR inhibitor, and a tyrphostin EGFR inhibitor.

Non-limiting examples of low molecular weight EGFR inhibitors suitable for use in practicing the methods of the invention include any of the EGFR inhibitors described in the following patent publications and all pharmaceutically acceptable salts and solvates of such EGFR inhibitors: European Patent Application No. EP 520722, issued December 30, 1992; European Patent Application No. EP 566226, issued on October 20, 1993; PCT International Publication No. WO 96/33980, issued on October 31, 1996; U.S. Patent No. 5,747,498 issued on Nov. 5, PCT Publication No. WO 96/30347, issued Oct. 3, 1996, and European Patent Application No. EP 787 772, issued on Aug. 6, 1997; PCT International Publication WO 97/30034; PCT International Publication WO 97/3 0044, published on August 21, 1997; PCT International Publication WO 97/38994, published on October 23, 1997; December 31, 1997 PCT International Publication No. WO 97/49688, published on Apr. 22, 1998, and European Patent Application No. EP 837063, issued on Jan. 22, 1998; PCT International Publication No. WO 98/02434, issued Jan. 22, 1998; Published PCT International Publication WO 97/38983; PCT published on July 27, 1995 Inter Publication WO 95/19774; PCT International Publication of the public July 27, 1995 WO 95/19970; April 1997 I7日公开之 PCT International 201 023 852 -115- 144535.doc Publication WO

97/13771; PCT International Publication WO 98/02437, published January 22, 1998; PCT International Publication WO 98/02438, published on January 22, 1998; PCT International Publication, published on September 12, 1997 WO 97/32881; German application published on January 29, 1998

19629652; PCT International Publication WO 98/33798 published on August 6, 1998; PCT International Publication WO published on September 12, 1997

97/32880; PCT International Publication WO 97/32880, published on September 12, 1997; European Patent Application EP 682027, published on November 15, 1995; published on January 23, 1997 (: 1' International Published Cases 0 97/02266; PCT International Publication WO 97/27199, published July 31, 1997; PCT International Publication WO 98/07726, published on Feb. 26, 1998; published on September 25, 1997 PCT International Publication WO 97/34895; PCT International Publication WO 96/31510, published October 10, 1996; PCT International Publication WO 98/14449, published on Apr. 9, 1998; published on April 9, 1998 PCT International Publication WO 98/14450; PCT International Publication WO 98/14451, published April 9, 1998; PCT International Publication WO 95/09847, published on April 13, 1995; May 29, 1997 PCT International Publication WO 97/19065; published PCT International Publication No. WO 98/17662, issued Apr. 30, 1998; U.S. Patent No. 5,789,427, issued on Aug. 4, 1998; issued on July 22, 1997 U.S. Patent No. 5,650,415; U.S. Patent No. 5,656,643 issued August 12, 1997; PCT International Publication No. WO 99/35146, issued July 15, 1999; July 15, 1999 PCT International Publication WO 99/35132; published PCT 144535.doc-116-201023852, published on February 18, 1999, International Publication No. WO 99/07701; and PCT International Publication WO 92, published on November 26, 1992 Other non-limiting examples of low molecular weight EGFR inhibitors include any of the EGFR inhibitors described in Traxler, P., 1998, Exp. Opin. Ther. Patents 8(12): 1599-1625. Specific preferred examples of the low molecular weight EGFR inhibitor used in the method include [6,7-bis(2-decyloxyethoxy)-4-quinazolin-4-yl]-(3-ethynylphenyl) Amine (U.S. Patent No. 5,747,498, issued May 5, 1998, and the aforementioned Moyer et al., 1997); C1-1033 and PD 183805 (Sherwood et al., 1999, Proc. Am. Assoc. Cancer Res. 40: 723); And ZD1839 (Woodburn et al., 1997, Proc. Am. Assoc. Cancer Res. 38: 633). Antibody-based EGFR inhibitors include any anti-EGFR antibody or antigen-binding fragment thereof that partially or completely blocks the natural ligand of EGFR to activate EGFR. Non-limiting examples of antibody-based EGFR inhibitors include Modjtahedi, H. et al, 1993, Br. J. Cancer 67: 247-253; Teramoto, T. et al, 1996, Cancer 77: 639-645; Goldstein et al. Human, 1995, Clin· Cancer Res. 1:1311-1318; Huang, SM et al., 1999, Cancer Res. 15:59(8): 1935-40; and Yang, X. et al., 1999, Cancer Res. Inhibitor as described in 59:1236-1243. Thus, the EGFR inhibitor may be a monoclonal antibody Mab E7.6, 3 (previously Yang, 1999) or Mab C225 (ATCC accession number HB-8508) or an antibody or antigen-binding fragment thereof having binding specificity. Other examples of antibody-based EGFR inhibitors include, for example, TARCEVA® (erlotinib), ERBITUX® (cetuximab), and Iressa® (gefitinib). 144535.doc -117- 201023852 Other antibody-based EGFR inhibitors can be administered to a host animal selected from, for example, pigs, cows, horses, rabbits, goats, sheep, and mice, according to known methods, with appropriate antigens or antigens. The decision base can be used to promote antibody production using various adjuvants known in the art (such as aluminum hydroxide, complete Freund's adjuvant, incomplete Freund's adjuvant, etc.) Antibodies suitable for use in practicing such methods include, but are not limited to, polyclonal antibodies, monoclonal antibodies, humanized antibodies, chimeric antibodies, human antibodies, and genetically engineered antibodies. "Anti-Zhao antigen binding moiety", "antigen-binding fragment", "antigen binding domain", "antibody fragment" or "functional fragment of antibody" are used interchangeably herein to refer to one or more residues of an antibody. A fragment that specifically binds to an antigen. Non-limiting examples of antibody fragments encompassed by such terms include, but are not limited to, Fab fragments, F(ab')2 fragments, Fd fragments consisting of VH and CH1 domains, Fv fragments, SCFv, scFv2 (both SCFv molecules are ligated in tandem with the dAb fragment (Ward et al., (1989) Nature 341:544 546); isolated CDRs; AVIMERTM; VH; VL; and single-stranded binding polypeptides (with immunoglobulins) FC fusion scFv). Also included in this definition is a "semi-" antibody comprising a single heavy chain and a single light chain. Other forms of single chain antibodies (such as bifunctional antibodies) are also encompassed herein. The "F(ab')2" and "Fab" portions can be produced by treating Ig with a protease such as pepsin and papain, and include the presence of two hinge regions between the two heavy chains. An antibody fragment produced by digestion of an immunoglobulin near a sulfur bond. For example, papain cleaves IgG upstream of the disulfide bond present between 144535.doc-118-201023852 in the hinge region of the two heavy chains, resulting in two homologous antibody fragments, VL and CL (light) The light chain formed by the constant region of the chain is linked to the heavy chain fragment composed of VH and (: Ηγ1 (γ-ΐ region in the heavy chain constant region) via a disulfide bond at its C-terminal region. The two homologous antibody fragments are called As a Fab. Pepsin is also downstream of the disulfide bond present between the hinge regions of the two heavy chains. The IgG is cleaved, resulting in an antibody fragment slightly larger than the fragment of the above two Fab' junctions in the hinge region. Called F(ab]2.

The Fab fragment also contains the constant domain of the light chain and the first constant domain ❹ (CH1) of the heavy chain. The Fab' fragment differs from the Fab fragment by the addition of several residues at the carboxy terminus of the heavy chain CH1 domain, including one or more cysteine acids from the antibody hinge region. Fab'-SH refers herein to a constant domain cysteinolic acid residue having a free thiol group Fab'. The F(ab')2 antibody fragment was originally produced as a pair of Fab' fragments having hinged cysteine between the two. Other chemical couplings of antibody fragments are also known.

"Fv" refers to an antibody fragment containing a complete antigen recognition site and an antigen binding site. This region consists of a dimer of a heavy chain variable domain that is tightly, non-covalently associated with a light chain variable domain. In this configuration, it is the three CDRs of each variable domain that interact to define an antigen binding site on the surface of the VH-VL dimer. In general, the combination of one or more CDRs of each VH and VL chain confers antigen binding specificity to the antibody. For example, it will be appreciated that, for example, CDRH3 and CDRL3 may be sufficient to confer antigen binding specificity to an antibody when it is transferred to a VH and VL chain of an acceptor antibody or antigen-binding fragment thereof, and the CDR combination can be tested using any of the techniques described herein. Combination, affinity, etc. Even a single variable domain (or a half-Fv comprising only three CDRs 144535.doc-119-201023852 specific for an antigen) has the ability to recognize and bind antigen, but may have lower affinity than the second variable domain. The affinity of time. Furthermore, although the two domains (VL and VH) of the Fv fragment are encoded by independent genes, they can be recombined by enabling them to be prepared as pairs of VL and VH regions to form a single protein chain of monovalent molecules (referred to as single strands). Fv (scFv) Bird et al, Science 242: 423-426 (1988); Huston et al, Proc. Natl. Acad. Sci. USA 85: 5879-5883 (1988); and Osbourn et al, Nat. Biotechnol. :778 (1998)) Synthetic linker ligation. Such scFvs are also intended to be encompassed by the term "antigen-binding portion" of an antibody. Any of the VH and ® VL sequences of a particular scFv can be ligated to the Fc region cDNA or genomic sequence to produce a representation vector encoding a complete Ig (e.g., IgG) molecule or other isotype. VH and VL can also be used to produce Fab, Fv or other Ig fragments using protein chemistry or recombinant DNA techniques. A "single bond Fv" or "sFv" antibody fragment comprises the VH and VL domains of an antibody where these domains are present in a single polypeptide chain. In some embodiments, the Fv polypeptide further comprises a polypeptide linker between the VH and VL domains that enables the sFv to form the desired structure for antigen binding. For a review of sFv, see, for example, Pluckthun,

The Pharmacology of Monoclonal Antibodies, Vol. 113, ed. Rosenburg and Moore, Springer-Verlag, New York, pp. 269-315 (1994). The term "AvimerTM" refers to a class of human-derived therapeutic proteins that are not associated with antibodies and antibody fragments and are composed of several modules and reusable binding domains (referred to as A-domains (also known as Class A modules, complementary). Type repeats or LDL receptor class A domains)). It is produced by the human extracellular receptor domain by in vitro exogenous 144535.doc •120· 201023852 sub-recombination and sputum (Silverman et al., 2005, Nat. Biotechnol. 23:1493-1494; Silverman. et al. , 2006, Nat. Biotechnol. 24:220). The resulting protein may contain multiple independent binding domains that exhibit improved affinity (in some cases, the concentration of the nanomolar) and specificity as compared to a single epitope binding protein. For example, see U.S. Patent Application Publication No. 2005/0221384, No. 2005/0164301, No. 2005/0053973, and No. 2005/0089932, No. 2005/0048512, and No. 2004/0175756, each of which is incorporated by reference in its entirety. The way is incorporated into this article. It is known that 217 human A domains each contain about 35 amino acids (about 4 kDa); and these domains are separated by a linker having an average length of 5 amino acids. The natural A domain is rapidly and efficiently folded into a uniform stable structure, which is mainly mediated by calcium binding and disulfide bond formation. This general structure requires a conserved backbone motif with only 12 amino acids. The end result is that a single protein chain contains multiple domains, each of which performs an independent function. The domains of the proteins are independently joined and the positive effects of each domain are additive. These proteins are referred to as "AvimersTM" and are derived from the affinity amerity multimer. The term "bifunctional antibody" refers to a small antibody fragment having two antigen binding sites comprising a heavy chain variable domain linked to a light chain variable domain (VL) in the same polypeptide chain (VH-VL). (VH). By using a linker that is too short to pair between the two domains on the same strand, the domains are paired with complementary domains on the other strand and two antigen-binding sites are created. Bifunctional antibodies are more fully described, for example, in EP 404,097; WO 93/11161; and Hollinger et al, Proc. Natl. Acad. Sci. USA 90:6444 6448 144535.doc-121-201023852 (1993). Antigen binding polypeptides also include heavy chain dimers, such as antibodies from camels and sharks. Camel and shark antibodies contain homodimerized pairs of two classes of V and C-like domains (both without light chains). Since the VH region of the heavy chain dimer IgG of Luocong does not need to interact hydrophobically with the light chain, the region in the heavy chain of the camel that normally contacts the light bond becomes a hydrophilic amino acid residue. The VH domain of the heavy bond dimer IgG is referred to as the VHH domain. The shark Ig-NAR comprises a homodimer of a variable domain (referred to as the V-NAR domain) and five C-like constant domains (C-NAR domain). In camels, the diversity of antibody lineages is determined by CDR 1, CDR 2 and CDR 3 in the VH or VHH regions. The CDR3 in the camel VHH region is characterized by its relatively long length, averaging 16 amino acids (Muyldermans et al., 1994, Protein Engineering 7(9): 1129). It is in contrast to the CDR3 region of antibodies from many other species. For example, the CDR3 of mouse VH has an average of 9 amino acids. A library of camel-derived antibody variable regions that maintains in vivo diversity of camel variable regions can be prepared by the methods disclosed in, for example, U.S. Patent Application Serial No. 20050037421. "Humanized" forms of non-human (e.g., murine) antibodies include chimeric antibodies containing minimal sequences derived from non-human Ig. In most cases, the humanized antibody is a human Ig (receptor antibody) in which one or more CDRs of the receptor are replaced with CDRs of a non-human species antibody (donor antibody) (such as having the desired specificity, affinity, and Binding to functional CDRs of mouse, rat, rabbit or non-human primate antibodies). In some cases, one or more of the FR amino acid residues of human Ig are replaced with the corresponding non-human amino acid residues. Furthermore, humanized antibodies may contain residues that are not present in the recipient antibody or in the donor antibody. These modifications can be made to improve antibody performance if required by 144535.doc -122- 201023852. A humanized antibody may comprise at least one, in some cases substantially all of the two variable domains, wherein all or substantially all of the hypervariable regions correspond to a hypervariable region of a non-human immunoglobulin, and in the FR All or substantially all of the FR of the human immunoglobulin sequence. The humanized antibody may optionally also comprise an immunoglobulin constant. At least a portion of the region (Fc), typically at least a portion of the human immunoglobulin constant region. For a detailed description, see Jones et al, Nature 321: 522-525 (1986); Reichmann et al, Nature 332: 323-329 (1988); and ❹ Presta, Curr. Op. Struct. Biol. 2: 593-596 (1992 〇 Monoclonal antibodies against EGFR can be prepared and isolated using any technique that produces antibody molecules from a continuous cell line in culture. Techniques for production and isolation include, but are not limited to, fusion tumor technology originally described by Kohler and Milstein (Nature, 1975, 256: 495-497); human B cell fusion tumor technology (Kosbor et al., 1983, Immunology Today 4: 72; Cote et al, 1983, Proc. Natl. Acad. Sci. USA 80: 2026-2030); and EBV_ win fusion tumor technology (Cole et al., 1985, Monoclonal Antibodies and 9

Cancer Therapy, Alan R. Liss, Inc., pp. 77-96). Alternatively, the techniques described for the production of single-chain antibodies (see, e.g., U.S. Patent No. 4,946,778) may be adapted to produce anti-EGFR single chain antibodies. Antibody-based EGFR inhibitors suitable for use in practicing the methods of the invention also include anti-EGFR antibody fragments, including, but not limited to, F(ab')2 fragments, which can be produced by pepsin digestion of intact antibody molecules; and Fab fragments, which can be Reduction of the disulfide bridge of the F(ab,)2 fragment is produced. Alternatively, Fab and/or scFv expression libraries can be constructed (see, for example, Huse et al., 1989, Science 246: 1275-1281) to allow 144535.doc-123-201023852 to rapidly identify fragments having the desired specificity for EGFR.

Techniques for the production and isolation of monoclonal antibodies and antibody fragments are well known in the art and are additionally described in Harlow and Lane, 1988, Antibodies : A

Laboratory Manual, Cold Spring Harbor Laboratory and J. W.

Goding, 1986, Monoclonal Anti-bodies: Principles and Practice, Academic Press, London. Humanized anti-EGFR antibodies and antibody fragments can also be prepared according to known techniques, such as those described in Vaughn, T. J. et al., 1998, Nature Biotech. 16:535-539 and references cited therein. The techniques, and such antibodies or fragments thereof, are also suitable for use in practicing the methods of the invention. Inhibitory small RNA (siRNA) can also serve as an EGFR inhibitor suitable for use in the methods of the invention. EGFR gene expression specifically inhibits the expression of EGFR (ie, RNA interference or RNAi) by contacting a tumor, individual, or cell with a double-stranded small RNA (dsRNA) or a vector or construct that produces a double-stranded small RNA. Come down. Methods for selecting appropriate dsRNA or dsRNA encoding vectors for sequences of known genes are well known in the art (see, for example, Tuschi, T. et al., (1999) Genes Dev. 13(24): 3191-3197; Elbashir, S. Μ. et al., (2001) Nature 411: 494-498; Hannon, GJ (2002) Nature 418: 244-251; McManus, Μ. T. and Sharp, PA (2002) Nature Reviews Genetics 3: 737-747; Bremmelkamp, TR et al., (2002) Science 296: 550-553; U.S. Patent Nos. 6,573,099 and 6,506,559; and International Patent Publication Nos. WO 01/36646, WO 99/32619, and WO 01/68836) . 144535.doc -124- 201023852 Ribonuclease can also serve as an EGFR inhibitor suitable for use in the methods of the invention. Ribonuclease is an enzymatic RNA molecule that is capable of catalyzing the specific cleavage of RNA. The mechanism of ribonuclease action involves the sequence-specific hybridization of a ribonuclease molecule to a complementary RNA-free sequence followed by endonucleolytic cleavage. Engineered hairpin or hammerhead ribonuclease molecules that specifically and efficiently catalyze the cleavage of the endonucleotide of the EGFR mRNA sequence are thus suitable for use within the scope of the methods of the invention. The specific ribonuclease cleavage site within any potential RNA target is initially identified by scanning the ribonuclease cleavage site of the target molecule. These cleavage sites typically include the following sequences: after GUA, GUU, and GUC ° identification, A short RNA sequence having between about 15 and 20 ribonucleotides corresponding to the cleavage site target gene region can be evaluated for predicted structural features (such as secondary structure) that may result in unsuitable nucleotide sequence recruitment . The suitability of a candidate target can also be assessed by testing its accessibility to hybridization with a complementary oligonucleotide using, for example, a ribonuclease protection assay. Various modifications can be introduced to the nucleotides of such methods as a means of increasing intracellular stability and half-life. Possible modifications include, but are not limited to, the addition of a ribonucleotide or deoxyribonucleotide flanking sequence to the 5' and/or 3' end of the molecule' or the use of a phosphorothioate or 2 in the oligonucleotide backbone. , -0-methyl instead of phosphodiesterase linkage. Antisense oligonucleotide constructs, siRNAs and ribonucleases suitable for use in the methods of the invention can be synthesized by a variety of known methods or methods developed in the future. For example, we may use chemical synthesis methods such as those using the proprietary ACE8 technology of Dharmacon, Inc. Alternatively, we can also use template-dependent synthesis. Synthesis may be carried out using modified or unmodified, 144535.doc-125-201023852 natural or non-natural bases as disclosed herein. In addition, the synthesis may or may not be carried out with modified or unmodified nucleic acid backbones as disclosed herein. In addition, antisense oligonucleotides can be synthesized in host cells by various known methods for synthesizing antisense nucleotide constructs, siRNA and ribonuclease molecules in host cells, and any methods developed in the future. Constructs, siRNA and ribonuclease. For example, antisense oligonucleotide constructs, siRNAs, and ribonucleases can be expressed by recombinant circular or linear DNA vectors using any suitable promoter. Suitable promoters for expressing an antisense or inhibitory RNA molecule from vectors suitable for such methods include, for example, the U6 or HI RNA pol III promoter sequence and the cellular giant viral promoter. The selection of other suitable promoters falls within the skill of this technology. Suitable carriers for use in the methods of the present invention include the vectors described in U.S. Patent No. 5,624,803, the disclosure of which is incorporated herein in its entirety. The recombinant plastids of these embodiments may also comprise an inducible or regulated promoter to express an antisense oligonucleotide construct, siRNA and ribonuclease in a particular tissue or in a particular intracellular environment. Antisense nucleotide constructs, siRNAs, and ribonucleases of the embodiments described herein can be represented by recombinant nucleic acid vectors in the form of two separate complementary RNA molecules or a single RNA molecule having two complementary regions. Suitable for selection of vectors expressing antisense oligonucleotide constructs, siRNAs and ribonucleases, methods for inserting nucleic acid sequences for expression of antisense oligonucleotide constructs, siRNAs and ribonucleases in vectors, and recombination Methods of delivery of the vector to the cell of interest are within the skill of the art. See, for example, Tuschl, T. (2002), Nat. Biotechnol, 20: 446-448; Brummelkamp TR et al. 144535.doc • 126· 201023852 person, (2002), Science 296: 550-553; Miyagishi et al., (2002) ), Nat. Biotechnol. 20: 497-500; Paddison PJ et al., (2002), Genes Dev. 16: 948-958; Lee NS et al., (2002), Nat. Biotechnol. 20: 500-505; Paul CP et al, (2002), Nat. Biotechnol. 20: 505-508 'the entire disclosure of which is incorporated herein by reference. Other methods for delivery and intracellular expression are described in, for example, U.S. Patent Application Publication No. 20040005593, No. 20050048647, No. 20050060771, the entire disclosure of which is incorporated herein by reference. In one embodiment, the EGFR inhibitor inhibits EGFR activity by at least about 2 fold, at least about 5 fold, at least about 10 fold, at least about 20 fold, and at least about 25 fold after contacting the cells with catechol butane. At least about 50 times, at least about 100 times or more than 100 times. In another embodiment, the inhibitor inhibits EGFR activity by at least about 5%, at least about 1%, at least about 15%, at least about 20%, at least about 50%, at least about 60%, at least about 70%, At least about 80 ° /. At least about 90%, at least about 95% or at least about 1%. In another embodiment, inhibition of EGFR arrests symptoms of a patient who has been administered a combination of catechol butane and an EGFR inhibitor. IGF-1R inhibitor resistance and inhibitor IGF-1R (type I insulin-like growth factor receptor) is the major binding 1 (317_1 but also binds IGF-II and insulin transmembrane RTK with lower affinity. IGF-1 and Receptor binding produces multiple cellular effects, including receptor recruitment, tyrosine kinase activation, intermolecular receptor autophosphorylation, and cytochemicalization of cell matrices such as IRS1 and She. Ligand-activated IGF-1R It also induces mitotic activity in normal cells and plays an important role in abnormal growth. The main physiological role of IGF-1 system is to promote normal growth and regeneration. Excessive expression of IGF-1R can cause mitosis, And promote ligand-dependent neonatal transformation. In addition, IGF-1R participates in the establishment and maintenance of malignant phenotype. It has been proved that several oncogenes affect the performance of IGF-1 and IGF-1R, and the decrease of true IGF-1R performance It is related to the resistance of transformation. Exposing cells to mRNA antisense to IGF-1R RNA can prevent soft agar growth of several human tumor cell lines. IGF-1R does not progress to cells in vivo and in vitro. Dead, and IGF-1R contains Reduction to below-type wild-type content causes tumor cell death in vivo. IGF-1R overexpression usually occurs in various tumors (breast, colon, lung sarcoma) and is usually associated with an invasive phenotype. High circulating IGF1 concentration is also associated with the prostate. Cancer, lung cancer and breast cancer risk. In addition, IGF-1R is involved in the establishment and maintenance of in vitro and in vivo transformed phenotypes (Baserga Εχρ Cell. Res·, 1999, 253, 1-6). IGF-lR kinase activity Participation in the transformation activities of several oncogenes (such as EGFR, PDGFR, SV40 T antigen, activated Ras, Raf and v-Src). The expression of IGF-1R in normal fibroblasts induces a neoplastic phenotype, which can then Tumors are formed in vivo. iGF_1r plays an important role in anchorage-independent growth. Igf_1R has also been shown to protect cells from chemotherapy, radiation and cytokine-induced death. Conversely, it has been shown to be dominant. Negative IGF-1R, triple helix formation or antisense expression vector inhibits endogenous IGF-1R and inhibits in vitro transformation activity and tumor growth in animal models. For example, resistance to EGFR inhibitors, tumor/cancer Resistant to IGF-1R inhibitors. 144535.doc -128· 201023852 In one embodiment, the method of the invention relates to the use of a compound that inhibits IGF-1R. The term "WF-1 Han inhibitor" as used herein. Refers to a number of 1GF·1 scale inhibitors, such as any chemical entity (eg, a small molecule) or biological entity (eg, antibodies, binding proteins, oligonucleotides, etc.) that, after administration to a patient, can inhibit the patient from Biological activity associated with IGF-1 receptor activation 'includes any further downstream biological effects caused by the binding of the natural ligand of IGF-1R to IGF-1R. IGF-1R kinase inhibitors include any agent that blocks IGF-1R activation or any downstream biological effect of IGF-1R activation associated with treating cancer in a patient. Exemplary modes of action of such inhibitors include, but are not limited to, direct binding to the intracellular domain of the receptor and inhibition of its kinase activity. Alternatively, an IGF-1R inhibitor can act by occupying a ligand binding site of the IGF-1 receptor or a portion thereof such that the receptor is inaccessible to its natural ligand to prevent or reduce its normal biological activity. Alternatively, an IGF-1R inhibitor can act by modulating the dimerization of an IGF-1R polypeptide or the interaction of an IGF-1R polypeptide with other proteins or promoting ubiquitination and endogenous degradation of IGF-1R. IGF-1R inhibitors can also act by reducing the amount of IGF-1 that can be used to activate IGF-1R by, for example, antagonizing the binding of IGF-1 to its receptor, reducing the level of IGF-1, or promoting IGF- 1 is associated with a non-IGF-1R protein, such as an IGF binding protein (eg, IGFBP3). IGF-1R inhibitors include, but are not limited to, low molecular weight inhibitors, antibodies or antibody fragments, antisense constructs, inhibitory small RNAs (e.g., RNA interference by dsRNA; RNAi) and ribonucleases. In one embodiment, the IGF-1R inhibitor is an organic small molecule or a monoclonal antibody that specifically binds to human IGF-1R. 144535.doc -129- 201023852 In one embodiment, the igf-ir inhibitor is an organic small molecule. Exemplary IGF-1R inhibitors include, but are not limited to, pmi嗤幷β than 1GF-1 kinetic kinase inhibitor, quinazoline IGF-1R kinase inhibitor, pyridinium pyrimidine IGF-1R kinase inhibitor, pyrimidine pyrimidine IGF -1R kinase inhibitor, pyrrole pyrimidine IGF_1R kinase inhibitor, pyridazole pyrimidine IGF-1R kinase inhibitor, phenylamino-pyrimidine IGF-1R kinase inhibitor, hydroxy guanidine IGF-1R kinase inhibitor, ° Levazole IGF-1R kinase inhibitor, pyridazine IGF-1R kinase inhibitor, isoflavone IGF-1R kinase inhibitor, quinolinone IGF-1R kinase inhibitor and tebuftine IGF-1R kinase inhibitor And all pharmaceutically acceptable salts and solvates of such IGF-1R kinase inhibitors. Other examples of IGF-1R inhibitors include the following IGF-1R inhibitors: International Patent Publication No. WO 05/037836 (imidazolium pyrimide IGF-IR^ enzyme inhibitor); International Patent Publication No. WO 03/ 018021 and WO 03/018022 (pyrimidine and pyrimidine-based compounds); International Patent Publication No. WO 02/102804 and WO 02/102805 (cyclolignan); International Patent Publication No. WO 〇2/〇92599 (pyrrolepyrimidine); International Patent Publication No. WO 01/72751 (pyrrolepyrimidine); and International Patent Publication No. WO 00/71129 (pyrrolidine triazine inhibitor); International Patent Publication No. WO 97/28161 (pyrrole [2,3-d]pyrimidine); Parrizas et al. (Endocrinology, 138: 1427-1433 with in vitro and in vivo IGF-1R inhibitory activity) (1997))); International Patent Publication No. WO 00/35455 (heteroaryl aryl urea); International Patent Publication No. WO 03/048133 (pyrimidine derivative); International Patent Publication No. WO 03/024967 No. WO 03/035614, 03/035615 144535.doc • 130· 201023852, 03/035616 And WO 03/035619 (compounds having an inhibitory effect on kinase proteins); International Patent Publication No. WO 03/068265 (Composition for treating hyperproliferative conditions); International Patent Publication No. WO 00/172 〇3 (pyrrolepyrimidine); Japanese Patent Publication No. JP 07/133280 (cephem compound); and Albert, A· et al., Journal of the Chemical Society, 11: 1540-1547 ( 1970) (^ pteridine and 4 unsubstituted bites). Other exemplary small molecule inhibitors include, but are not limited to, OSI-906 (OSI) ® and XL228 (Exelixis). In one aspect, the IGF-1R inhibitor can be a small molecule inhibitor. Exemplary small molecule inhibitors include, but are not limited to, 〇SI-906 (OSI) and XL228 (Exelixis). OSI-906 (OSI) can be administered at different schedules of administration and administration, such as: (1) oral administration of one or two doses per dose until the disease develops or unacceptably toxic (up to 21 days); (2) Start treatment with S1 (every 14 曰 曰 曰 曰), and start S2 after seeing clinically significant toxicity >1 at level 2 (every 14 曰 1-5 曰 per Once a day). Similarly, S3 (1-7 每 every 14 days) was started after the clinically significant toxicity >2 in the S2 was observed. In each schedule, a single dose is administered on each designated day, and then until the 14th is a drug-free period. XL228 (Exelixis) can be administered at the following different dosing and dosing schedules, such as intravenous administration 1 hour a week. Other specific examples of IGF-1R inhibitors which may be used in accordance with the methods of the invention include h7C10 (Centre. de Recherche Pierre Fabre), an IGF-1 antagonist; EM-164 (ImmunoGen Inc.), an IGF-1R modulator; 144535.doc -131 - 201023852 CP-751871 (Pfizer Inc.), IGF-1 antagonist; lanreotide (Ipsen), an IGF-1 antagonist; IGF-1R oligonucleotide (Lynx Therapeutics Inc) .); IGF-1 Oligonucleotide (National Cancer Institute); IGF-1R protein cool amine kinase inhibitor developed by Novartis (eg NVP-AEW541, Garcia-Echeverria, C. Et al, (2004) Cancer Cell 5:231-239; or NVP-ADW742, Mitsiades, CS et al, (2004) Cancer Cell 5:221-230); IGF-1R protein tyrosine kinase inhibitor (Ontogen Corp) AG-1024 (Camirand, A. et al., (2005) Breast Cancer Research 7: R570-R579 (DOI 10.11 86/bcrl028); Camirand, A. and Pollak, M., (2004) Brit J. Cancer 90:1825-1829; Pfizer Inc.; IGF-1 antagonist; telfutin AG-538 and I-OMe-AG 538; BMS-536924, a small molecule of IGF-1R Formulation; &amp; PNU-145 15 6E (Pharmacia &amp; Upjohn SpA), an IGF-1 antagonist. Antibody-based IGF-1 R inhibitors include any anti-IG F -1R antibody or antigen-binding fragment thereof that partially or completely blocks the natural ligand of IGF-1R to activate IG F -1R. Antibody-based IGF-1R inhibitors also include any anti-IGF-1 antibody or antibody fragment that partially or completely blocks IGF-1R activation. Non-limiting examples of antibody-based IGF-1R inhibitors include Larsson, 0 et al, (2005) Brit. J. Cancer 92: 2097-21 01 and Ibrahim, Υ·H. and Yee, D. (2005) Clin. Cancer Res. 11; Inhibitors described in 944s-950s; monoclonal antibody IMC-A12 developed and tested by the National Cancer Institute; commercially developed antibodies, including antibodies to Imclone (eg A12), Amgen antibodies (AMG479) or Schering-Plough Research 144535.doc -132- 201023852

The antibodies of the Institute (e.g., 19D12); and the antibodies described in U.S. Patent Application Publication No. US 2005/0136063 A1 and US 2004/0018191 A1. The IGF-1R inhibitor may be a monoclonal antibody, a polyclonal antibody, or an antibody or antibody fragment having binding specificity. Exemplary monoclonal antibodies include, but are not limited to, AMG-479 (Amgen), BIIB022 (Biogen), IMC-A12 (ImClone), • CP-751, 871 (Pfizer), SCH-717454 (Schering), R-1507 (Roche ) and MK-0646 (Merck). The terms "antigen-binding portion of an antibody", "antigen-binding fragment", "antigen® binding domain", "antibody fragment" or "functional fragment of antibody j" are used interchangeably herein to refer to one or more retention specificities of an antibody. Fragments that bind to the ability of the antigen. Non-limiting examples of antibody fragments encompassed by such terms include, but are not limited to, Fab fragments, F(ab')2 fragments, Fd fragments consisting of VH and CH1 domains, Fv fragments , scFv, scFv2 (series of two scFv molecules connected end to end in the bond), dAb fragment (Ward et al, (1989) Nature 341:544 546); isolated CDR; AVIMERTM; VH; VL; A chain-binding polypeptide (scFv fused to an immunoglobulin Fc). This definition additionally includes a "semi-" antibody comprising a single heavy bond and a single light bond. Other forms of single chain antibodies (such as bifunctional antibodies) are also encompassed herein. The "F(aiy)2" and "Fab" portions can be produced by treating Ig with proteases such as pepsin and papain, and include disulfide bonds present between hinge regions of the two heavy bonds. Antibody fragments produced by digestion of immunoglobulins nearby. For example, papain cleaves IgG upstream of the disulfide bond present between the hinge regions of the two heavy chains, resulting in two homologous antibody fragments, of which light consists of VL and CL (light chain constant region) The chain is linked to a heavy chain fragment consisting of vh and 144535.doc-133-201023852 CHyl (gamma-indenyl region in the heavy chain constant region) via a disulfide bond at its C-terminal region. These two homologous antibody fragments are each referred to as Fab. The gastric protease also cleaves the IgG&apos; downstream of the disulfide bond present between the hinge regions of the two heavy chains to produce an antibody fragment that is slightly larger than the two Fab-linked fragments in the hinge region. This antibody fragment is referred to as F(ab')2.

The Fab fragment also contains the constant domain of the light chain and the first constant domain (CH1) of the heavy chain. The Fab·fragment differs from the Fab fragment by the addition of several residues at the carboxy terminus of the heavy chain CH1 domain, including one or more cysteine acids from the antibody hinge region. Fab'-SH refers herein to a Fab having a free thiol group of a cysteine residue of a constant domain. The F(ab,)2 antibody fragment was originally produced as a Fab with a hinged cysteine between the two, in the form of a fragment pair. Other chemical couplings of antibody fragments are also known. "Fv" refers to an antibody fragment containing a complete antigen recognition site and an antigen binding site. This region consists of a dimer of a heavy, non-covalently associated heavy bond variable domain and a light chain variable domain. In this configuration, it is the two CDRs of each variable domain that interact to define an antigen binding site on the surface of the VH.VL dimer. In general, one or more of the CDRs of each VH and VL chain confer antigen binding specificity to the antibody. For example, it will be appreciated that, for example, CDRH3 and CDRL3 may be sufficient to confer antigen binding specificity to an antibody when it is transferred to a VH and VL chain of an acceptor antibody or antigen-binding fragment thereof, and the CDR combination can be tested using any of the techniques described herein. Combination, affinity, etc. Even if a single variable domain (or a half-Fv comprising only three CDRs specific for an antigen) has the ability to recognize and bind antigen, the affinity may be lower than the affinity when combined with the second variable domain. Furthermore, although the two 144535.doc-134.201023852 domains (VL and VH) of the Fv fragment are encoded by independent genes, they can be recombined by enabling them to be prepared as pairs of VL and VH regions to form a single unit of monovalent molecules. Protein bond (referred to as single-chain Fv (scFv) Bird et al, Science 242: 423-426 (1988); Huston et al, Proc. Natl. Acad. Sci. USA • 85: 5879-5883 (1988); and Osbourn Et al., Nat. Biotechnol. . 16:778 (1998)) Synthetic linker ligation. Such scFvs are also intended to be encompassed by the term "antigen-binding portion" of an antibody. Any of the VH and VL sequences of a particular scFv can be ligated to the Fc region cDNA or genomic sequence to produce an expression vector encoding a β Ig (e.g., IgG) molecule or other isotype. VH and VL can also be used to produce Fab, Fv or other Ig segments using protein chemistry or recombinant DNA techniques. A "single-chain Fv" or "sFv" antibody fragment comprises the VH and VL domains of an antibody, wherein such domains are present in a single polypeptide chain. In some embodiments, the Fv polypeptide further comprises a polypeptide linker between the VH and VL domains that enables the sFv to form the desired structure for antigen binding. For a review of sFv, see, for example, Pluckthun, The Pharmacology of Monoclonal Antibodies, Vol. 113, Rosenburg and Moore, ed., Springer-Verlag, New York, pp. 269-315 (1994). The term "AvimerTM" refers to a class of human-derived therapeutic proteins that are not associated with antibodies and antibody fragments and are composed of several modules and reusable binding domains (referred to as A-domains (also known as Class A modules, Complementary repeat sequence or LDL receptor class A domain)) composition. It is produced by ex vivo exon remodeling of human extracellular receptor domains and by sputum cells (Silverman et al., 2005, Nat. Biotechnol. 23: 1493-1494; Silverman et al., 2006, Nat. 144535.doc -135- 201023852

Biotechnol. 24:220). The resulting protein may contain multiple independent binding domains that exhibit improved affinity (in some cases, the concentration of the nanomolar) and specificity as compared to a single epitope binding protein. See, for example, U.S. Patent Application Publication No. 2005/0221384, No. 2005/0164301, No. 2005/0053973, and No. 2005/0089932, No. 2005/0048512, and No. 2004/0175756, each of which is incorporated by reference in its entirety. Incorporated herein, 217 human A domains each comprise about 35 amino acids (about 4 kDa); and the domains are separated by a linker having an average length of 5 amino acids. The natural A domain is rapidly and efficiently folded into a uniform stable structure, which is mainly mediated by calcium binding and disulfide bond formation. This general structure requires a conserved backbone motif with only 12 amino acids. The end result is that a single protein chain contains multiple domains, each of which performs an independent function. The domains of the proteins are independently joined and the positive effects of each domain are additive. These proteins are referred to as "AvimersTM" and are derived from avidity multimers. The term "bifunctional antibody" refers to a small antibody fragment having two antigen binding sites comprising a heavy chain variable domain linked to a light chain variable domain (VL) in the same polypeptide chain (VH-VL). (VH). By using a linker that is too short to pair between the two domains on the same strand, the domains are paired with complementary domains on the other strand and two antigen-binding sites are created. Bifunctional antibodies are more fully described, for example, in EP 404,097; WO 93/11161; and Hollinger et al, Proc. Natl. Acad. Sci. USA 90:6444 6448 (1993). Antigen-binding polypeptides also include heavy chain dimers, such as antibodies from camel and shark 144535.doc-136. 201023852. Camel and shark antibodies contain homodimerized pairs of two classes of v and c-like domains (both without light chains). Since the VH region of the heavy chain dimer IgG in camel does not need to interact hydrophobically with the light chain, the region in the heavy chain of the camel that normally contacts the light chain becomes a hydrophilic amino acid residue. The VH domain of the heavy chain dimer IgG is called the VHH domain. The shark Ig-NAR contains a homodimer of a variable domain (referred to as the V-. NAR domain) and five C-like constant domains (C-NAR domain). In camels, the diversity of antibody lineages is determined by CDR 1, CDR 2 and CDR 3 in the VH or VHH regions. The CDR3 in the camel VHH region is characterized by its relatively long length of length, with an average of 16 amino acids (Muyldermans et al., 1994, Protein Engineering 7(9): 1129). It is in contrast to the CDR3 region of antibodies from many other species. For example, the CDR3 of mouse VH has an average of 9 amino acids. A library of camel-derived antibody variable regions that maintains in vivo diversity of camel variable regions can be prepared by the methods disclosed in, for example, U.S. Patent Application Serial No. 20050037421. "Humanized" forms of non-human (e.g., murine) antibodies include chimeric antibodies containing minimal sequences derived from non-human Ig. In most cases, the humanized antibody is a human ig (receptor antibody) in which one or more of the CDRs are replaced by a CDR of a non-human species antibody (donor antibody) (such as having the desired specificity, affinity, and Binding to functional CDRs of mouse, rat, rabbit or non-human primate antibodies). In some cases, one or more of the FR amino acid residues of human Ig are replaced with the corresponding non-human amino acid residues. Furthermore, humanized antibodies may contain residues that are not present in the recipient antibody or in the donor antibody. These modifications can be made to improve antibody performance if desired. A humanized antibody may comprise at least one, in some cases substantially all of the two variable domains, 144535.doc -137-201023852 wherein all or substantially all of the hypervariable regions correspond to the height of the non-human immunoglobulin The variable region, and all or substantially all of the FR are the FR of the human immunoglobulin sequence. The humanized antibody may optionally also comprise at least a portion (Fc) of the constant region of the immunoglobulin, typically at least a portion of the human immunoglobulin constant region. For a detailed description, see Jones et al, Nature 321 : 522-525 (1986); Reichmann et al, Nature 332: 323-329 (1988); and Presta, Curr. Op. Struct. Biol. 2: 593-596 (1992) . Monoclonal antibodies against IGF-1R can be prepared and isolated using any technique that produces antibody molecules from successive cell lines in culture. Techniques for production and isolation include, but are not limited to, fusion tumor technology originally described by Kohler and Milstein (Nature, 1975, 256: 495-497); Human B cell fusion tumor technology (Kosbor et al., 1983, Immunology Today 4: 72; Cote et al, 1983, Proc. Nati· Acad. Sci. USA 80: 2026-2030); and EBV-fused tumor technology (Cole et al., 1985, Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, Inc. , pp. 77-96). Alternatively, the techniques described for the production of single-chain antibodies (see, e.g., U.S. Patent No. 4,946,778) may be adapted to produce anti-IGF-1R single chain antibodies. Antibody-based IGF-1R kinase inhibitors suitable for use in practicing the methods of the invention also include anti-IGF-1R antibody fragments, including but not limited to F(aV)2 fragments, which can be digested by pepsin to intact anti-IGF-1R body molecules Produced; and a Fab fragment that can be produced by reducing the disulfide bridge of the F(alV)2 fragment. Alternatively, Fab and/or scFv expression libraries can be constructed (see, for example, Huse et al., 1989, Science 246: 1275-1281) to allow rapid identification of fragments having the desired specificity for IGF-IR. 144535.doc -138- 201023852 Techniques for the production and isolation of monoclonal antibodies and antibody fragments are well known in the art and are described in Harlow and Lane, 1988, Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory and JW Goding, 1986, Monoclonal Antibodies: Principles and Practice, Academic Press, London. Humanized anti-IGF-1R antibodies and antibody fragments can also be prepared according to known techniques, such as those described in Vaughn, TJ et al, 1998, Nature Biotech. 16:535-539 and references cited therein. And such antibodies or fragments thereof are also suitable for use in practicing the methods of the invention. In one aspect, the IGF-1R inhibitor can be a monoclonal antibody or an antigen-binding fragment thereof. Exemplary monoclonal antibodies include, but are not limited to, VIII]^〇-479(Amgen) &gt; BIIB022(Biogen) ' IMC-A12(ImClone) ' CP-75 1,871 (Pfizer) ' SCH-717454(Schering) &gt; R-1507 (Roche) and MK-0646 (Merck). On Days 1, 15 and 29, AMG-479 (Amgen) can be administered intravenously (IV) at an increased dose over 1 hour. Patients who were evaluated at week 8 and who showed an objective tumor response or stable disease continued treatment at 57th. The treatment is repeated every 2 weeks without disease progression or unacceptable toxicity. BIIB022 (Biogen) can be administered intravenously every 3 weeks until disease progression or unacceptable toxicity. IMC-A12 (ImClone) can be administered at different schedules and administration schedules, such as: (1) intravenous administration of a dose of 10 mg/kg every 2 weeks for 1 hour. Patients should continue treatment until disease progression or unacceptable toxicity; (2) intravenous administration of 10 mg/kg every 2 weeks for 1 hour; (3) cycle on day 1 on day 1, 144535.doc -139- 201023852 Intravenous administration of 6 mg/kg on days 8 and 15; (4) intravenous administration of 3 mg/kg over 6 () minutes per week; (5) on the 8th, 15th and 22nd Nikkei i hour intravenous administration. In the absence of disease progression or unacceptable toxicity, the treatment process can be repeated every 28 days for up to 2 years; (6) once a week for intrauterine administration. Continue treatment with no disease progression or unacceptable toxicity; or (7) intravenous administration over the first day, the 8th day, and the 15th day. The treatment is repeated every 21 days without disease progression or unacceptable toxicity. CP-751, 871 (Pfizer) can be administered at different dosages and administration schedules, such as: (1) 17 cycles in the range of 6 to 3,000 years old to (9) mg/kg on the first day of each cycle Total (leap year); (2) study the second work in the circulation and 2 〇 mg/kg intravenously, and every three weeks (from the first la) and (3) after 2.5 hours Intravenous administration of 2 mg/kg up to 17 cycles; (4) intravenous administration of 20 mg/kg every 3 weeks; (5) administration of 20 mg/kg intravenously in each of the 21-day cycles; 6) Intravenous administration of 6, 1 or 20 mg/kg every three weeks; (7) Intravenous administration of 2 //kg in the first sputum of each 21 曰 cycle; (8) Intravenous injection every 21 days Up to 6 cycles; (9) intravenous administration on the first day of each 28-day cycle until disease progression or toxicity; (丨〇) 20 mg/kg administered intravenously in the first sputum of each 28-day cycle until Disease progression or unacceptable toxicity; (11) 20 mg/kg every 3 weeks for 17 cycles until disease progression or unacceptable toxicity occurs; or (12) 5 hours intravenously on Days 1 and 22 SCH-717454 (Schering) can be administered and administered differently Degree of administration such as: intravenous administration every 2 weeks until the disease develops. R-1507 (R〇che) can be administered with the following different administration and administration schedules, 144535.doc •140- 201023852 as (1) per Weekly intravenous administration of 3 or 9 doses, administered intravenously no more than 16 mg / kg per week; (2) weekly or every 3 weeks starting with mg / kg intravenously with an increased dose; and (3) Intravenous administration of 9 mg/kg per week. MK-0646 (Meixk) can be administered with the following different administrations and administration schedules, such as: (1) weekly intravenous administration of 1 mg per hour /kg; (Intravenous administration of 7.5, 10 or 15 mg/kg via sputum; (3) Intravenous administration of increased dose per week to 2 hours: h25, 2.5, 5.0, 10·0, 15 〇 and 2〇〇mg/kg. Each patient receives an increased dose. The patient then enters a different dosing regimen: every other week or every three weeks; (in the first period, according to the dose limit Toxicity, weekly intravenous administration of 5 mg/kg increased to 10 mg/kg per week, followed by consideration of this dose. In the π phase; weekly intravenous administration of 5 mg/kg; (5) weekly intravenous injection With 5 or 1 at a time Mg/kg over a continuous period of time; (6) intravenous dose of 1 hour to 2 hours per week: 1.25, 2.5, 5.0, 1 〇. 〇, 15.0 and 2 〇. 〇 mg / kg duration 4 Continuous weeks; φ and (7) increased doses consisting of the initial dose (1〇ading d〇se) (2.5, 5.0 '1〇.〇, 15.〇, 20.0 and 30.0 mg/kg) followed by The dose is maintained every other week starting at two weeks after the completion of the initial dose (at least 25 mg/kg) = or 'The IGF-1R kinase inhibitor suitable for use in the methods of the invention may be based on antisense nucleotide constructs. Antisense oligonucleotides (including antisense RNA molecules and antisense DNA molecules) function to directly block IGF_1R mRNA translation by binding to IGF-1R mRNA and thereby preventing protein translation, or increasing mRNA degradation, This reduces the amount of IGF_1R kinase protein and is achieved by reducing the activity in the cells by 144535.doc -141 - 201023852. For example, an antisense raised nucleotide having at least about 15 bases and complementary to a unique region encoding an mRNA sequence of IGF·1R can be synthesized, for example, by a conventional acid diester technique, and by, for example, a vein Intra-injection or infusion administration. Methods of using antisense technology to specifically inhibit gene expression of a gene whose sequence is known are well known in the art (see, for example, U.S. Patent No. 6,566,135; No. 6,566,131; No. 6,365,354; No. 6,410,323; 6,107,091; 6,046,321; and 5,981,732). Inhibitory small RNA (siRNA) can also serve as an IGF-1R kinase inhibitor suitable for use in the methods of the invention. IGF-1R gene expression specifically inhibits the expression of IGF-1R by contacting tumors, individuals or cells with double-stranded small RNAs (dsRNAs) or vectors or constructs that produce double-stranded small RNAs (ie, RNA) Interference or RNAi) to reduce. Methods for selecting an appropriate dsRNA or dsRNA encoding vector for a gene of known sequence are well known in the art (see, for example, Tuschi, T. et al., (1999) Genes Dev. 13(24): 3191-3197; Elbashir, SM et al. Human, (2001) Nature 411: 494-498; Hannon, GJ (2002) Nature 418: 244-251; McManus, Μ. T. and Sharp, PA (2002) Nature Reviews Genetics 3: 737-747; Bremmelkamp, TR (2002) Science 296: 550-553; U.S. Patent Nos. 6,573,099 and 6,506,559; and International Patent Publication Nos. WO 01/36646, WO 99/32619 and WO 01/68836). Ribonuclease can also serve as an IGF-1R kinase inhibitor suitable for use in the methods of the invention. Ribonuclease is an enzymatic RNA molecule that catalyzes the specificity of RNA 144535.doc -142- 201023852. The ribonuclease mechanism involves the sequence-specific hybridization of the ribonuclease molecule to the complementary standard RN A followed by endonucleolytic cleavage. Engineered hairpin or hammerhead ribonuclease molecules that specifically catalyze the cleavage of the endonucleolytic cleavage of the IGF-IR mRNA sequence are thus suitable for use in the context of the methods of the invention. The specific ribonuclease cleavage site within any potential RNA target is initially identified by scanning the ribonuclease cleavage site of the target molecule. These cleavage sites typically include the following sequences: GUA, GUU, and GUC. After identification, the predicted structural features (such as secondary structures) that may cause the oligonucleotide sequence to be unsuitable may be evaluated to have between about 15 and 20 ribonucleotides corresponding to the cleavage site target gene region. Short RNA sequence. The suitability of the candidate stem can also be assessed by testing the accessibility of the hybridization to the complementary oligonucleotide using, for example, a ribonuclease protection assay. Various modifications can be introduced into the oligonucleotides as a means of increasing intracellular stability and half-life. Possible modifications include, but are not limited to, the addition of a ribonucleotide or a deoxyribonucleotide flanking sequence to the 5, and/or 3 ends of the molecule, or the use of a phosphorothioate or 2' in the nucleus frame. -0-methyl instead of diacetate linkage. Antisense oligonucleotide constructs, siRNAs and ribonucleases suitable for use in the methods of the invention can be synthesized by a variety of known methods or methods developed in the future. 】°° people can use chemical synthesis, such as using Dharmacon,

The exclusive ACE method of IllC. Alternatively, we can also use template-dependent synthesis. Synthesis can be carried out using modified or unmodified, natural or unnatural bases as described herein. In addition, the synthesis may or may not be carried out with modified or unmodified nucleic acid backbones as disclosed herein. 144535.doc 143 - 201023852 In addition, it can be synthesized in host cells by various known methods for synthesizing antisense oligonucleotide constructs, siRNA and ribonuclease molecules in host cells and any methods developed in the future. Antisense oligonucleotide constructs, siRNA and ribonuclease. For example, antisense oligonucleotide constructs, siRNAs, and ribonucleases can be expressed by recombinant circular or linear DNA vectors using any suitable promoter. Suitable promoters for expressing an antisense or inhibitory RNA molecule from a suitable vector include, for example, the U6 or HI RNA pol III promoter sequence and the cellular giant viral promoter. The selection of other suitable promoters is within the skill of the art. Suitable carriers for use in embodiments of the present invention include those described in U.S. Patent No. 5,624,803, the disclosure of which is incorporated herein in its entirety by reference. Such recombinant plasmids may also comprise an inducible or regulated promoter to express antisense nucleotide constructs, siRNA and ribonuclease in a particular tissue or in a particular intracellular environment. Antisense nucleotide constructs, siRNAs, and ribonucleases can be expressed by recombinant nucleic acid vectors in the form of two independent complementary RN A molecules or a single RNA molecule having two complementary regions. Suitable for the selection of vectors expressing antisense oligonucleotide constructs, siRNAs and ribonucleases, insertion of nucleic acid sequences for expression of antisense nucleotide constructs, siRNA and ribonuclease in vectors, and recombination Methods for delivery of vectors to cells of interest are within the skill of the art. See, for example, Tuschl, T. (20〇2), Nat. Biotechnol, 20: 446-448; Brummelkamp TR et al, (2002), Science 296: 550-553; Miyagishi M #A, (2002), Nat. Biotechnol 20: 497-500; Paddison PJ et al., (2002), Genes Dev. 16: 948-958; Lee NS et al., (2002), Nat. Biotechnol. 144535.doc 201023852 20: 500-505; CP et al. (2002), Nat. Biotechnol. 20: 505-508, the entire disclosure of which is incorporated herein by reference. Other suitable methods for delivery and intracellular expression are described, for example, in U.S. Patent Application Publication No. 20040005593, No. 20050048647, No. 20050060771, the entire disclosure of which is incorporated herein by reference. In one embodiment, the IGF-1R inhibitor inhibits IGF-1R activity by at least about 2 fold, at least about 5 fold, at least β about 10 fold, and at least about 20 fold after contacting the cells with catechol butane. At least about 25 times, at least about 50 times, at least about 100 times or more than 100 times. In another embodiment, the inhibitor inhibits the activity of IGF-1R by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 50%, at least about 60%, at least about 7 Å. %, at least about 80%, at least about 90%, at least about 95% or at least about. In another embodiment, inhibition of IGF-IR arrests symptoms of a patient who has been administered a combination of catechol butane and an IGF-1R inhibitor. Administration of EGFR Inhibitors and 1GF-1R Inhibitors Although several embodiments of IGF-IR inhibitors and EGFR inhibitors are administered as described above, it will be appreciated that other dosage regimens may be used. In various embodiments, there is a synergistic effect between catechin and butane and IGF-1R inhibitors and/or EGFR inhibitors, which allows administration of lower doses of catechol butane, IGF-1R inhibitors and / or EGFR inhibitors. In some embodiments, the synergy between the IGF_1R inhibitor and/or the EGFR inhibitor allows for a lower dose of tea to be given to the calcined. In some embodiments, the synergistic effect between the IGF_丨R inhibitor and/or EGFR inhibitor and catechol butane allows for the administration of lower doses of IGF-1R inhibitors at 144535.doc • 145· 201023852 and / or EGFR inhibitors with catechin butane. In some embodiments, the synergy between the IGF-1R inhibitor and/or EGFR inhibitor and catechol butane allows administration of the IGF·1R inhibitor and/or EGFR inhibitor at a lower frequency. In some embodiments, the synergy between the IGF-IR inhibitor and/or the EGFR inhibitor and the catechin is such that catechol butane can be administered at a lower frequency. In some embodiments, the synergy between the IGF-1R inhibitor and/or the EGFR inhibitor and the catechins allows the administration of IGF-1R inhibitors and/or EGFR inhibitors and catechol at a lower frequency. Butane. In some embodiments, a therapeutically effective amount of an IGF-IR inhibitor and/or an EGFR inhibitor is administered to a patient. In some embodiments, the drug can be administered repeatedly, for example, twice daily progress, daily progress, every other day progress, every three days progress, four-day progress, weekly progress, bi-weekly progress, monthly progress Wait. In some embodiments the 'IGF-1R inhibitor and/or EGFR inhibitor is administered for one, two, three, four, five, six weeks or more at one of the above schedules. In some embodiments, this round of follow-up is followed by a period of non-administration of the IGF-1R inhibitor and/or EGFR inhibitor (clearing period), which may be 1, 2, 3, 4 weeks or more. In some embodiments, the scavenging period is from about 1 day to about 3 weeks, or from about 3 days to about 1 week or from about 1 week to about 2 weeks, or from about 2 weeks to about 3 weeks. In some embodiments, the IGF-IR inhibitor and/or the qixin inhibitor are administered twice a week for 4 weeks, followed by an i, 2 or 3 week washout period. In some embodiments, the IGF-IR inhibitor and/or EGFR inhibitor is administered every 2, 3 or 4 weeks for 4 weeks, followed by a 1, 2 or 3 week washout period. In some embodiments, the IGF-1R inhibitor and/or EGFR inhibitor is administered once a week for 4 weeks, followed by a ^, 144535.doc-146.201023852 2 or 3 week washout period. In some embodiments, the zgf-1R inhibitor and/or EGFR inhibitor is administered twice a week for 6 weeks&apos; followed by a 1, 2 or 3 week washout period. In some embodiments, the IGF-IR inhibitor and/or EGFR inhibitor is administered every 2, 3 or 4 days for 6 weeks, followed by a 1, 2 or 3 week washout period. In some embodiments, the IGF-IR inhibitor and/or EGFR inhibitor is administered once a week for 6 weeks&apos; followed by a 1, 2 or 3 week washout period. In some embodiments, the IGF-IR inhibitor and/or EGFR inhibitor is administered twice a week for 2 weeks, followed by a 1, 2, or 3 week washout period. In some embodiments, the IGF_1R inhibitor and/or EGFR inhibitor is administered every 2, 3 or 4 历 for 2 weeks, followed by a 1, 2 or 3 week washout period. In some embodiments, the IGF_丨R inhibitor and/or EGFR inhibitor is administered once a week for 2 weeks, followed by a 1, 2, or 3 week washout period. In some embodiments, uniform administration of an IGF-1R inhibitor and/or an EGFR inhibitor can be used. Suitable uniform doses encompassed herein are about 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55 per dose. 60, 65, 70, 75 mg/m2 or any integer of IGF-1R inhibitor and/or EGFR inhibitor contained therein. Or 'the uniform dose encompassed herein is about 55, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50 per dose. , 55, 60, 65, 70, 75 '80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 140, 150, 160, 170, 180, 190, 200 mg/kg or Any integer of IGF-1R inhibitor and/or EGFR inhibitor included therein. Such doses can be administered in one of the administration schedules described herein. In some embodiments, the dosing schedule is administered daily, every other day, twice a week, 144535.doc -147 - 201023852 times, or every two weeks (every other week)

Weekly (0.5, 1, 2, 30, 35, 40, 45, IGF-1R inhibitors and /. EGFR inhibitors per week, depending on the circumstances, insert a pause period after a specific number of dosing cycles. In other embodiments , about 0.5, 1, 2, 3, 4, 5, on a daily, every other day, twice a week, weekly (weekly) or biweekly (every other week) dose schedule. 6, 7, 8, Q, 1 0, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110 , 115, 120, 125, 130, 140, 150, 160, 170, 180, 190, 200 mg/kg or any integer included therein, optionally with a pause period (interruption) after a specified number of dosing cycles In some embodiments, the total weekly dose ranges from about 14 mg/m2 to about 525 mg/m2. In various embodiments, the total weekly dose ranges from about 12 mg/m2 to about 450 mg/m2, or From about 10 mg/m2 to about 375 mg/m2, or from about 8 mg/m2 to about 300 mg/m2. In some embodiments, the total weekly dose ranges from about 6 mg/m2 to about 225 mg/m2. In some embodiments, each Dosages range from about 4 mg/m2 to about 150 mg/m2, or from about 2 mg/m2 to about 75 mg/m2. In some embodiments, the weekly dose ranges from about 3.5 mg/m2 to about 350 mg/m2. Or from about 3.0 mg/m2 to about 300 mg/m2, or from about 2.5 mg/m2 to about 250 mg/m2, or from about 2.0 mg/m2 to about 200 mg/m2 or from about 1.5 mg/m2 to about 150 mg/ M2, or from about 1.0 mg/m2 to about 100 mg/m2, or from about 0.5 mg/m2 to about 5 mg/m2. In certain embodiments, a therapeutically effective amount of a 1GF_1R inhibitor and/or 144535. Doc • 148-201023852 EGFR inhibitor is about 0.5-50 mg/m2. In some embodiments, a therapeutically effective amount of an IGF-1R inhibitor and/or an EGFR inhibitor is about 2-75 mg/m2. Butane can be administered concurrently with an IGF-1R inhibitor and/or an EGFR inhibitor. Alternatively, catechol butane can be administered prior to the IGF-1R inhibitor and/or EC3FR inhibitor. • In some embodiments The appropriate dose of the IGF-1R inhibitor and/or EGFR inhibitor is administered intravenously every 3 hours for 3 hours and is repeated every 3 weeks. In some embodiments, the dose is between 45 mg/m2 per course. Each treatment range is 135 10 mg/m2. Kits The compounds described herein can be packaged in kits. In some embodiments, provided herein is a kit comprising catechol butane in a dosage form, particularly for oral or intravenous administration. In some embodiments, the kit further comprises an IGF-IR inhibitor in a dosage form, particularly for oral or intravenous administration. Alternatively or additionally, the kit further comprises an EGFR inhibitor in a dosage form of φ, particularly for oral or intravenous administration. In a particular embodiment, the catechol butane and the 1 (31?-111/[17] scale inhibitor are in separate dosage forms. In some embodiments, the kit includes one or more doses of the button for oral administration. In the form of a catechol butane. However, in other embodiments, the catechol butane may be in a variety of dosage forms, such as capsules, caplets, gel caps, powders for suspension, and the like. In some embodiments, the kit comprises one or more doses of an IGF-1R/EGFR inhibitor in the form of a lozenge for oral administration. However, in other embodiments, the or 144535.doc - 149- 201023852 The same dose of IGF-1R/EGFR inhibitor can be in a variety of dosage forms, such as capsules, caplets, gel caps, powders for suspension, etc. The container components of the kit should generally include at least one vial, test tube, The flask, vial, syringe and/or other container component can be placed with at least one polypeptide, and/or preferably suitably aliquoted. The kit can include components that contain at least one fusion protein, detectable moiety, reporter molecule And/or strictly limit any of the commercial sales Other reagent containers. These containers may include injection molded and/or blow molded plastic containers in which the required vials are stored. The kit may also include printed materials for use of the kit _ substances. The packaging and kits may be additionally dispensed in medicine. Buffering agents, preservatives and/or stabilizers are included. The components of the kit can be sealed in individual containers, and all of the various cereals can be in a single package. The kit can be used for cold storage. Alternatively, the formulation may contain a stabilizer such as bovine serum albumin (BSA) to extend the shelf life of the kit. If the composition is lyophilized, the kit may contain other agents for recovery. Such medicinal preparations; acceptable reconstituted solutions are well known in the art and include, for example, pharmaceutically acceptable phosphate buffered saline (PBS). Additionally, the packages or kits provided herein may be Also included is any other portion provided herein such as one or more reporter molecules and/or - or multiple detectable moieties/agents. The armor and kit may additionally include one or more components for the following assays: ^ EUSA Verification, Cytotoxicity assay, ADP-ribosyltransferase activity determination, etc. The samples to be tested in the 4 cases include, for example, blood blood accumulation and 144535.doc 201023852 tissue sections and secretions, urine, sputum sputum, drinking Chinese heterosexuals Packaging and kits may additionally include one or more components for receiving #^果口口0 (eg syringes, cups, cotton swabs, etc.) Packaging and kits may additionally include, for example, product description or treatment adaptation The label of the disease may be included in any of the compositions described herein for the treatment of any of the indications described herein.

The term "packaging material" refers to the physical structure in which the components of the kit are placed. The packaging material can keep the components sterile' and can be made from materials commonly used for such purposes (e. g., paper, corrugated fiber, glass, plastic, foil, ampoules, etc.). The label or package insert may include appropriate written instructions. Thus the kit may additionally include labels or instructions for using the kit components in any of the methods described herein. The kit can include a compound in a package or dispenser and instructions for administering the compound in a manner described herein. In some embodiments, the kit comprises at least three dosage forms, one comprising phytobutane, one comprising an IGF-IR inhibitor, and the other comprising a ♦ EGfr inhibitor. In some embodiments, the kit includes a dose sufficient for a period of time. In some particular embodiments, each dose is physically separated in a compartment in which each dose is separated from other doses. In some embodiments, the &quot;set comprises at least two dosage forms, one comprising catechin and one comprising an IGF-IR inhibitor or an EGFR inhibitor. In some embodiments, the kit includes a dose sufficient for a period of time. In a particular embodiment, each dose is physically separated in a compartment where each dose is separated from other doses. In a particular embodiment the 'set is preferably a blister pack. The blister pack is known from the art of 144535.doc - 151 - 201023852, and is located on the side of the hall. The compartments individually include a transparent B with a compartment (foam or blister): 7 Dosage; and backing materials such as paper, yoshi, which are easy to remove so that each dose can be obtained from the blister pack without disturbing other doses. In some embodiments, the kit can be a blister pack&apos;, each dose of tea is expected to be Dingxuan, - Μ inhibition! and the EGFR inhibitor is separated from the other doses in separate foaming or blistering orders. In some of these embodiments, the blister pack can have apertures that allow it to be smashed with other sputum knives by tearing apart the rest of the package. from. Separate foaming may contain separate dosage forms. The advantage of separating the active pharmaceutical ingredients in separate foaming may be that they prevent separate dosage forms (e.g., tablets and capsules) from contacting and destroying each other during shipping and handling. In addition, separate dosage forms and/or separate dosage forms can be obtained for administration to patients at different times. In some embodiments, the third active pharmaceutical ingredient can be in the form of a liquid or reconstitutable powder that can be sealed separately (eg, in vials or vials) and subsequently inhibited with a separate dose of catechol butane, IGF_1R And packaging of the foaming package of the inhibitors. In some embodiments, the formulation and/or EGFR inhibitor is in the form of a liquid or reversible powder, which is sealed separately (for example in vials or ampoules). And then packaged with a blister pack containing a separate dose of catechol butane. These examples should be particularly useful in the following clinical scenarios where a specified dose of catechol butane, IGF- is used with the following schedule of administration. 1R inhibitors and EGFR inhibitors: wherein the IF inhibitor is administered to the illuminant at the same or different days and the EGFR inhibitor is administered on the same or different day. It can also be packaged as 144535.doc -152-201023852, which is suitable for providing a synergistic effect or a sequelae treatment effect and a description of each active agent. In his embodiment, the kit may be a separate compartment. container, These compartments have separate covers that are suitable for opening at a specific schedule. For example, the set '' can contain boxes with seven compartments (or similar containers), each of which is used in the middle of the week. Days, and each compartment is marked to indicate the day of its correspondence: In some specific embodiments, each compartment is further subdivided to separate the active pharmaceutical ingredient from the other species. Said that the separation is advantageous in that it prevents damage to the dosage form and allows for different time administration and labeling of the effect. The container may also comprise a dosage schedule suitable for providing a synergistic or sequelae therapeutic effect. Instructions for a plurality of active agents. The kit may also include instructions for using the kits according to various methods and methods described herein, including, for example, scientific references, package insert materials, clinical trial results, and/or Its summary and similar information, 贫 讯 '' indicates or establishes the activity and / or advantages of the composition, and / or its description for music, drug administration, side effects, drug interactions, and investment The disease condition used by the compound or other information suitable for health care providers (health coffee pr〇vider). This information can be based on the results of various studies such as the use of experimental animals involving in vivo models and human clinical trials. In various embodiments, the kits described herein may be provided, sold, and/or promoted to health care personnel (including physicians, nurses, pharmacists, prescribers (formulary 〇fficiai), and the like). In some embodiments, the kit can be sold directly to the consumer. In some embodiments, the packaging material 144535.doc • 153· 201023852 material: a container containing the composition and optionally a label attached to the container The kit optionally includes other components such as, but not limited to, a syringe for administering the composition. The instructions may include practice of any of the methods (including methods of treatment described herein). The monthly book may additionally include an indication of a satisfactory clinical endpoint or any adverse symptoms that may occur, or a regulatory agency (such as a US food) Additional information for human subjects required by the Food and Drug Administration (Food and Drug Administrati〇n). It can be said that the moon can be on the printed matter, such as on a set of paper or cardboard attached to the set or on a label attached to the set or packaging material or attached to the vial or tube of the containment kit. Instructions may also be included on the following computer readable media: such as discs (floppy or hard disc), optical CDs (such as CD- or dvD-ROM/ram), magnetic tape, electrical storage media (such as ram and ROM) IC tip And mixtures thereof (such as magnetic/optical storage media). In some embodiments, the kit can include an agent that detects the amount of DNA, RNA or protein present in the sample of the patient's tumor cells to be treated. In some aspects, the kit can contain reagents and materials for any of the assays described herein. EXAMPLES The present application can be fully understood by reference to the following non-limiting examples, which are provided as exemplary embodiments of the present application. The following examples are provided to more fully illustrate the embodiments, but should not be construed as limiting the scope of the application in any way. Although specific embodiments of the present application have been shown and described herein, it is apparent that the embodiments are provided by way of example only. Familiarity 144535.doc • 154-201023852 Various changes, modifications, and alterations are possible to those skilled in the art; it is understood that the various methods described herein can be used to practice the methods described herein. Example 1: Treatment of basal cell epithelial pain This example describes the clinical study of human patients diagnosed with basal cell epithelial tumors, the anti-caries life of catechol-butane-containing compositions. • catechins can be prepared for topical administration to treat basal cell epithelioma. The lesion surface tape was peeled off before each application. The test drug was applied directly to the lesion with a coating approximately 2 mm thick and covered with a dressing. After at least seven days, a second application was made according to the investigator's decision. Dosages range from 20-350 mg/cm2 with up to 5 mg/cm2 for deep tumors. To determine the effect of the test compound on malignant neoplasms, the excised biopsy was obtained 30 days after the initial treatment. Example 2: Treatment of actinic keratosis A human patient diagnosed with actinic keratosis was treated with a catechol butane composition prepared for topical application. The test composition was applied directly to the lesion with a coating approximately 2 mm thick and confined to the edge of the lesion. The dressing is applied to the lesion. The lesions were visually inspected and measured 7 and 14 days after the initial treatment. At the discretion of the investigator, a second treatment can be performed with the same test compound. To determine whether the test compound can remove the anterior malignant neoplasm, a biopsy is obtained 30-60 days after the initial treatment. If the biopsy is reported as negative, ie no tumor, then the patient is examined every 6 months for recurrence for 2 months. Example 3: Treatment of Tumor Lesions 144535.doc -155- 201023852 A canine patient suffering from various tumor lesions is treated with a catechol-butane composition prepared for topical application. The animals were allowed to move for two hours or the animals were allowed to move for two hours with a sedative (eg, 0.03 mg oxymorphone/lb2 and atropine sulfate). After clamping, washing, and measuring the size of the tumor, the surface of the skin is abraded until bleeding. To facilitate penetration of the test composition into large or subcutaneous tumors, a 20 or 22 gauge needle was used to pierce the tumor. After blotting the skin's blood, the tumor site was covered with a 1-2 mm test composition coating with a peripheral extension of 5 mm. After 2 hours, wipe off the compound and gently clean the area. The test composition was applied up to three times in a two week interval or until the tumor was cleared. Example 4: Inhibition of HUVEC Growth and 3H-Thymidine Incorporation Assay The inhibition of cell growth can be assessed using a variety of assays. In one example, HUVECs were cultured in a C02 incubator in a 75 cm2 flask (Falcon, Becton-Dickinson, Franklin Lakes, NJ) at 37 °C under subconfluent conditions. The cells were detached by incubation for 15 minutes at 37 ° C with Hanks' balanced salt solution with 15 mM EDTA in 25 mM HEPES buffer (pH 7.3). After washing twice with ice-cold PBS, the cells were resuspended in endothelial cell growth medium at a concentration of 25,000 cells per ml. In other experiments, human umbilical vein endothelial cells (HUVEC) were suspended and cultured in endothelial cell growth medium without FBS and bovine brain extract. An aliquot of 200 μΐ cell suspension was inoculated into each well of a 96-well culture plate. Cells were incubated overnight at 37 ° C in a CO 2 incubator, followed by NDGA or sterile PBS in triplicate. The plates were kept in the incubator for 72 hours during which time 144535.doc -156-201023852 was replaced with fresh medium and NDGA/PBS every 24 hours. 3H-thymidine (1 μM) was added to each well and the plate was incubated for 20 hours. The cells were washed with PBS, and then treated with 1 μM of trypsin-EDTA (0.05% trypsin, 0.53 mM EDTA) per well for 1 minute at 37 °C. Cells were harvested on a glass fiber filter paper (Wallac Printed Filtermat A) using a collector 96 (TOMTEC, Hamden, CT) and assayed for 3H-radioactivity in a Trilux 1540 MicroBeta liquid scintillation and luminescence counter (Wallac, Turku, Finland). Example 5: In vivo treatment of human breast cancer The in vivo anti-tumor effect of catechol butane on [VIX-1 (human breast cancer) cells was determined. Male or female athymic BALB/C mice were used, which were 6 to 8 weeks old and weighed 20 to 35 grams. MX-1 cells were cultured in standard RPMI-1640 medium, and subcutaneously implanted into the flank of nude mice to propagate tumor strains. Nude mice were implanted with 25 mg MX-1 solid tumor fragments. Experiments were performed using tumors ranging from 25-l 〇〇 mm2. Test compound (0.1 mL) was injected directly into the tumor. The tumor is periodically measured to determine its weight, which is calculated by using the length (L) of the tumor multiplied by the width (W) by the height (H). This procedure was repeated at regular intervals until 60 days after the initial treatment or all mice had died. Mice that did not display tumor evidence were housed for 60 days to assess the likelihood of tumor recurrence, and tumor characteristics (if any) were recorded when the tumor recurred. Example 6: Anti-cancer therapy for pre-formation of human breast cancer tumors The anti-cancer effects of catechol butane described herein on pre-formed human breast cancer tumors in human skin transplanted in SCID mice can be assessed. Doc -157- 201023852 The role of Ding. In short, 'When human full-thickness skin (killing _ _ Skhl) transplanted in SCID gas has no signs of inflammation, contraction or rejection, MCF-7 cells (8xl〇6 cells in n1 nU PBS) are skinned. Internally transplanted into such grafts. Mice were treated until apparently palpable tumors (in most cases (1) - diameter. The mice with significant _ mice were divided into arrays for therapeutic studies. Intravenous to the control animals via the tail vein (iv) Administration of sterile PBS. Administration of 5 (10, 10 mg/kg, 25 mg/kg or 5 〇 catecholbutane) to the test animals group (4 mice per mouse (10).) via the tail vein. To be administered: once a week; twice a week; three times a week for three weeks, one week off; two times a day for three weeks, one week off; or three times a day for three weeks, one week off. The group was tested for the combination of catechol butane with the formulation, IGF-1R inhibitor or a combination of the two. During the treatment, the tumor size and pathology of the mice were monitored daily. The electronic balance was used twice a week (OHAUStm model GT210) Weigh the mice and measure the tumor size three times a week using an electronic caliper (PRO-MAX 6 吋 caliper; Fowler Co Newton, Mass) connected to a computer using the OptoDemoTM software (Fowler c〇). The following formula converts the measured tumor diameter into Tumor volume: V = length X width X height χ π / 6. Student's t-test (Student's t-test) statistical analysis data were used to compare different mouse groups. Example 7: SCID mouse model of ovarian cancer to determine catechol The ability of butane to treat ovarian cancer can be used in SCID mice. 144535.doc -158- 201023852 Briefly, ovarian cancer cells are implanted into SCID mice to produce ovarian tumors. The mice with established tumors were treated with pegylated butane at an increased dose (starting at 5 mg per kg body weight). Control animals were treated with sterile pBS. Additional mouse groups could be added to test catechol butane with EGFR inhibitor, IGF-IR inhibitor or combination therapy with both. Mice were monitored and tumor growth was measured by weekly sacrifice of animals. Tumors were measured as described above. Example 8: SCID mouse model of renal cancer is To determine the ability of catechol butane to treat kidney cancer, a kidney cancer cell line can be used in SCID mice. Briefly, 'renal cancer cells are implanted into SCID mice to produce kidney tumors. Increased by intravenous administration Dosage (starting at 5 mg per kg body weight) Phenol butane treatment of mice with established tumors. Control animals were treated with sterile pBS. Additional mouse groups could be added to test catechins with EGFR inhibitors, IGF-1R inhibitors or a combination of the two Mice were monitored and tumor growth was measured by weekly sacrifice of animals. Limbs were measured as described above. Example 9: SCID mouse model of myeloma to determine the ability of catechol butane to treat myeloma, can be small in SCID A bone tumor cell line was used in the mouse. Briefly, myeloma cancer cells were implanted into SCID mice to produce myeloma. A group of mice with established tumors was treated by intravenous administration of an increased dose (starting at 5 mg per kilogram of body weight). Control animals were treated with sterile pBS. Additional groups of mice can be added to test the combination therapy of catechin with 144535.doc-159-201023852 EGFR inhibitor, IGF-1R inhibitor or both. Mice were monitored and tumor growth was measured by weekly sacrifice of animals. Tumors were measured as described above. Example 10: Toxicology in Rhesus Monkeys Rhesus monkeys were used in the study to address the toxicology of NDGA. Briefly, monkeys were given 5.0 mg/kg, 10.0 mg/kg, 25.0 mg/kg, 50 mg/kg or 100 mg/kg NDGA weekly for three weeks. Placebo animals were dosed with the appropriate solution at the same rate without NDGA. The dose is administered by intravenous injection in 30 to 60 minutes, and at least 6 animals are administered in each dose. Toxicology is assessed via one or more of the following: body weight measurements, basic physiological clinical measurements, serial serum chemistry, hematology assessment, and histopathological evaluation. Example 11: Human Clinical Trial of Safety and Efficacy of Catechol Butane Objective: To assess the safety and pharmacokinetics of catechol butane (e.g., NDGA) administered. Study Design: This should be Phase I: a single center, open-label, randomized dose escalation study, followed by a Phase II study in cancer patients with biopsy disease. Patients should not be exposed to catechol butane (eg NDGA) prior to entering the study. The patient is unacceptable for the treatment of his cancer within 2 weeks of the start of the trial. Treatment includes the use of chemotherapy, hematopoietic growth factors, and biological therapies (such as monoclonal antibodies). The exception to this is the use of hydroxyurea for patients with white blood cell (WBC) number &gt; 30xl03^L. Due to the relatively short-lived nature of most anti-leukemia agents, this duration seems to be sufficient to remove. The patient must recover from all toxicity associated with previous treatment (Da or Level 1). Evaluate all 144535.doc • 160· 201023852 individual safety and collect all blood collections for pharmacokinetic analysis as scheduled. All studies were performed with the permission of the institutional ethics committee and the patient's consent. Stage I: The patient is given catechol butane (e.g., NDGA) according to a predetermined dosing schedule. Groups with 3-6 patients were given an increased dose of NDGA until the maximum tolerated dose (MTD) of the combination of NDGAs was determined. The test dose range was initially determined by establishing individual dose ranges for NDGA. The MTD is defined as the dose before the dose-limiting toxicity of 2 of 2 or 6 of 3 patients. Dose-limiting toxicity is determined according to the definitions and criteria set by the National Cancer Institute (NCI) Common Terminology for Adverse Event (CTCAE) version 3.0 (August 9, 2006). NDGA can be administered in different doses and administration schedules. The catechol butane (e.g., NDGA) is administered in an amount such that the area under the mean plasma concentration curve is from about 25 to about 700 ng.h/mL. Catechol butane (e.g., NDGA) can also be administered to achieve an average maximum plasma concentration of between about 1 and about 50 ng/ml. The test dose range is initially determined by establishing a range of individual doses for the patient. For the treatment of prostate cancer, NDGA is administered orally to the patient twice daily at 1-28 ;; treatment is repeated every 28 在 without disease progression or unacceptable toxicity. Alternatively, 2000 mg NDGA can be administered orally to the patient daily. Alternatively, NDGA is administered intravenously to the patient on day 1-5; treatment is repeated every 28 days in the absence of disease progression or unacceptable toxicity. To treat solid tumors of epithelial origin, NDGA was administered to the patient intravenously 144535.doc -161 - 201023852 every 24 hours. The dose starts at 100 mg/hr (24 hours 2400 mg) in 5 groups of 3 to 6 patients in increments of 25 mg per hour to a maximum of 200 mg/hr (24 hours 4800 mg) or up to Determine the MTD. To treat refractory solid tumors (such as malignant tumors of the head and neck), NDGA is administered intravenously to the patient weekly, initially for three weeks. The target is increased by the initial dose to a target of 20 mg per cubic centimeter of tumor volume. In the case of putative tolerance, continue to increase the dose so that the group can be treated for 6 weeks, and finally 8 weeks; or, every 28 曰 can be intravenously administered to patients with solid tumors refractory to EGFR inhibitors or IGF-1R inhibitors The NDGA voted for five consecutive weeks. To treat recurrent advanced gliomas, NDGA is administered intravenously to patients. Groups with 3-6 patients received an increased dose of NDGA until the MTD was determined. The MTD is the dose before the dose-limiting toxicity of 2 or 3 of the 6 patients. To treat leukemia, NDGA was administered intravenously to the patient three times a week for two weeks, followed by a week. Adverse events and toxicity were assessed prior to each treatment cycle and when clinically indicated. Determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT). The dose will increase from 1000 mg to 15 00 and 2200 mg, or to 500 mg if 1000 mg exceeds MTD. Stage II: Patients were enrolled in the NDGA as indicated in stage I of the MTD as defined in stage I. The treatment is administered as described in Phase I as described above in the absence of disease progression or unacceptable toxicity. After completing one or more of the study therapy procedures, the patient achieving all or part of the response may be subjected to one or more other treatment procedures. Complete the study treatment 144535.doc •162- 201023852 2 After the patient has paid more than 2 cases, the patient may receive other treatments or multiple treatments during the development of the disease, subject to the initial eligibility criteria. Sputum sampling: A series of blood is drawn through a direct vein and puncture before and after administration of catechu. A venous blood sample (5 mL) was obtained at approximately ίο min and after administration at the time of administration for the determination of ▲ concentration: 1 2 3, 4, 5, 6, 7 and 14. Each serum sample can also be divided into two aliquots at a later time point. All serum samples were treated as -20. (:下) Transporting serum samples on dry ice. Pharmacokinetics: Collect patient plasma/serum samples for pharmacokinetics before starting treatment and at 1, 2, 3, 4, 5, 6, 7 and 曰4曰Evaluation. Samples can also be collected at a later point in time. The most recent version of the m〇AVL software is used by the modd independent method.

Equipment Corporati〇n νΑχ 86〇〇 Calculates pharmacokinetic parameters on a computer system. The following pharmacokinetic parameters were determined: peak serum concentration (cmax); time to peak peak concentration (tmax); area under time concentration curve (auc) from time zero to last blood sampling time (auc 〇 72), It is calculated by means of the linear trapezoidal rule; and the terminal elimination half-life Gw), which is calculated by excluding the rate constant. The rate constant is excluded by linear regression of continuous data points in the terminal linear region of the log-linear concentration time curve. The mean, standard deviation (SD) and coefficient of variation (cv) of the pharmacokinetic parameters are calculated for each therapy. ). Calculate the ratio of the mean values of the parameters (preserved formulati〇n/preservative-free formulation). 144535.doc •163· 201023852 Patient response to therapy: assessment of patient response by X-ray, CT scan and/or MRI imaging, and imaging before starting the study and at the end of the first cycle, and every four weeks or subsequent cycles Re-image at the end. Imaging modalities were selected based on cancer type and feasibility/availability, and the same imaging modality was used for similar cancer types and during each patient study procedure. The reaction rate was determined using the RE. CIST standard. (Therasse et al., "/· iVai/. Cancer / ί. 2000 Feb 2; 92(3): 205-16; and the World Wide Web site: ctep.cancer.gov/forms/TherasseRECISTJNCI.pdf). The patient was also subjected to a cancer/tumor biopsy to assess progenitor cancer cell phenotype and community growth changes by flow cytometry, Western blotting, and IHC, and cytogenetic changes were assessed by FISH. After completing the study treatment, the patient was periodically followed for 4 weeks. The statistical significance of the test results was assessed. Example 12: Clinical Trial of Osteosarcoma This example describes a randomized, blind, placebo-controlled, multi-center, phase II study designed to provide a preliminary assessment of the safety and efficacy of NDGA in patients with myeloma. . About 1 to about 800 patients participated, of which about 50 to about 400 patients were assigned to the treatment group' and about 50 to about 400 patients were assigned to the placebo group. The test will consist of intravenous administration or oral administration of NDGA as described above in Example 11. The time frame for the study is estimated to be from about 6 months to about 5 years, with the respondents indicated at the end of the initial study continuing treatment. Other results are measured as follows: First outcome measure: Total response rate. One of the goals of this study was to demonstrate a total response rate of about 40°/. (Use placebo) increase to approximately 60% (or 60°/.) (using NDGA). 144535.doc 164· 201023852 The second outcome measure measurable includes response duration, tumor deterioration time, overall survival, severity, and non-severe adverse events. For example, treatment can prevent disease progression (ie, stagnation) or can lead to improvement. Other or additional, other goals may be measured with respect to one or more of the following: reduced tumor burden, reduced new management, reduced side effects, reduced adverse reactions, and/or increased patient compliance. Example I3: Clinical Trial of Kidney Cancer This example describes a randomized, blind, placebo-controlled, multicenter 'π phase study designed to treat women with NDGA in patients with renal cell carcinoma (kidney cancer) A preliminary assessment of sexuality and efficacy is provided. Approximately one to about one patient participated, with about 50 to about 4 patients assigned to the treatment group and about 50 to about 400 patients assigned to the placebo group. The test will consist of intravenous administration or oral administration of NDGA as described above in Example 11. The time frame for the study is estimated to be from about 6 months to about 5 years, with the responders indicated at the end of the preliminary study continuing treatment. Other results are measured as follows: φ First-result measure: no deterioration of survival. One of the goals of this study was to demonstrate that progression-free survival was approximately 14-18 months (or longer) in the MiNDGA group from approximately 9-13 months in the placebo group. The first outcome measure of beta sputum includes duration of response, time to tumor progression, overall survival, severity, and non-severe adverse events. For example, treatment can prevent disease progression (i.e., stagnation) or can lead to improvement. Other or additional measurements may be made with respect to one or more of the following: reduced tumor burden, reduced neovascularization, reduced side effects, reduced adverse reactions, and/or increased patient compliance. 144535.doc • 165-201023852 Example I4: Clinical Trial of Hepatocellular Carcinoma This example describes a randomized, blind, placebo-controlled, multicenter, π-phase study designed to treat NDGA with renal cell carcinoma (kidney) A preliminary assessment of the fullness and efficacy of women in patients with cancer). Approximately 8 (10) patients participated, with approximately 50 to approximately 400 patients assigned to the treatment group and approximately 50 to approximately 400 patients assigned to the placebo group. The test will consist of intravenous administration or oral administration of NDGA as described above in Example 11. The time frame for the study was estimated to be approximately 6 months 'about 5 years' in which the responders indicated at the end of the preliminary study continued treatment. The other results are measured as follows: The first measure is no deterioration. One of the goals of this study was to demonstrate that progression-free survival increased from approximately 3-9 months in the placebo group to approximately 6-12 months (or longer) in the ndga group. The second outcome measure that can be evaluated includes duration of response, time to tumor progression, overall survival, severity, and non-severe adverse events. For example, treatment can prevent disease progression (ie, stagnation) or can lead to improvement. Other or additional measurements may be made regarding one or more of the following: reduced tumor burden, reduced neovascularization, reduced side effects, reduced adverse reactions, and/or increased patient compliance. Example 15: Clinical Trial of Ovarian Cancer This example describes a randomized, blind, placebo-controlled, multi-center, π-phase study designed to provide a preliminary assessment of the safety and efficacy of NDGA in patients with ovarian cancer. . About 1 · about 8 患者 patients participated, of which about 50 to about 400 patients were assigned to the treatment group, and about 5 约 about 400 patients were assigned to the placebo group. The trial will consist of intravenous, intradermal or oral administration of NDGA as described above in the example 144535.doc • 166· 201023852. The time frame for the study is estimated to be from about 6 months to about 5 years, with the respondents who indicated at the end of the preliminary study continue treatment. Other outcome measures are as follows: First-Results Measure: No deterioration of survival. The aim of the study was to demonstrate that progression-free survival increased from approximately 3-6 months in the placebo group to the ndga group. Approximately 4-12 months (or longer). The second outcome measure measurable includes duration of response, time to tumor progression, overall survival, severity, and non-severe adverse events. For example, treatment can prevent disease progression (i.e., stagnation) or can lead to improvement. Other or additional measurements may be made regarding one or more of the following: reduced tumor burden, reduced neovascularization, reduced side effects, reduced adverse reactions, and/or increased patient compliance. Example 16: Clinical Trial of Ovarian Cancer Combination Therapy This example describes a randomized, blind, placebo-controlled, multi-center, π-phase study designed to combine NDGA with Topotecan in patients with ovarian φ cancer Provide a preliminary assessment of safety and efficacy. Approximately 100 to approximately 800 patients participated, of which approximately 5 to about 400 patients were assigned to the treatment group&apos; and approximately 50 to approximately 400 patients were assigned to the placebo group. The trial consisted of a combination of NDGA administered intravenously with repeated doses as described above in Example u as described above in Example u with intravenous infusion of Topotecan at approximately 1.5 mg/m2 'where the course of treatment was repeated during the study . Topotecan and placebo were administered to control patients. The time frame for the study is estimated to be from about 6 months to about 5 years, with the responders indicated at the end of the preliminary study continuing treatment. Other outcome measures are as follows: 144535.doc -167- 201023852 First outcome measure: no deterioration of survival. One of the goals of this study was to demonstrate that progression-free survival increased from approximately 3-6 months in the Topotecan plus placebo group to approximately 6-12 months (or longer) in the Topotecan plus NDGA group. The second outcome measure measurable includes duration of response, time to tumor progression, overall survival, severity, and non-severe adverse events. For example, treatment can prevent disease progression (i.e., stagnation) or can lead to improvement. Other or additional measurements may be made regarding one or more of the following: reduced tumor burden, reduced neovascularization, reduced side effects, reduced adverse reactions, and/or increased patient compliance. Example 17: NDGA (TT-IOO) inhibition of multiple anti-cancer targets in vitro The inhibition of lipoxygenase activity was determined by using a fat oxygenase inhibitor screening assay kit (Cayman Chemicals, Ann Arbor, MI). Purified 15-LOX (soy) was incubated with different concentrations of TT-100 followed by the addition of arachidonic acid or linoleic acid. The LOX activity is determined by quantifying the amount of hydroperoxide produced by colorimetric readings. Inhibition of RTK activity was determined by ELISA as follows. TT-100 was incubated with a recombinant protein representing the IGF-1R or EGFR kinase domain (Cell Signaling Technology, Danvers, ΜΑ) for 5 minutes, followed by the addition of guanidine (10 μΜ) and biotinylated peptide (IRS, respectively) The -1 sequence or ΡΤΡ1Β) (0.2 μΜ) was reacted for 45 minutes. The reaction was stopped with 50 mM EDTA, and the biotin-binding substrate was captured on a 96-well coated streptavidin plate. The captured tyrosine phosphate was determined by incubation with HRP-conjugated anti-acidic acid antibody (Santa Cruz Biotechnology, Santa Cruz, CA) and colorimetric readings on a 96-well plate reader. Chemical. 144535.doc -168- 201023852 NDGA (TT-1 0) directly inhibits the tyrosine kinase activity of purified IGF-1R and EGFR with greater affinity than its effect on purified lipoxygenase (LOX). Example 18: NDGA (TT-IOO) in vitro inhibition of Iressa resistance NSCLC cells Η 1975 NSCLC cells expressing EGFR Τ790Μ mutations were cultured for 3 days in the presence of 10 μΜ Iressa or 10 μΜ TT-100. Cell content was measured and expressed as the percentage growth of control cells grown without Iressa and ΤΤ-1 00. As shown in Figure 2, ΤΤ-100 inhibited the proliferation of Iressa-resistant NSCLC cells expressing the EGFR Τ790Μ mutation. In the presence of ΤΤ-100, the proliferation of Η1975 NSCLC cells was reduced by approximately 50% » HI299 NSCLC cells were cultured in the absence or presence of 1 μΜ Iressa with or without 1 μ μΜ or 20 μΜ ΤΤ-100. Cell content was measured and expressed as the percentage growth of control cells grown without Iressa and TT-100. As shown in Figure 3, H1299 NSCLC cells were resistant to clinically deliverable concentrations of Iressa. ΤΤ-100 alone inhibited the proliferation of H1299 NSCLC cells, especially when used at 20 μM. In addition, ΤΤ-100 and clinical concentration of Iressa have synergistic effects in these drug-resistant NSCLC cells because cell proliferation is further reduced in the presence of Iressa and ΤΤ-100. Iressa resistant cells Η1975 or Η1299 NSCLC cells were also grown in soft agar for 8 days without or with 5 μΜ or 30 μΜ ΤΤ-100. Colony formation was assessed and compared to control cells grown without sputum-100. As shown in Figure 4, ΤΤ-100 inhibited the colony formation of Iressa resistant Η1975 and Η1299 NSCLC cells. Cell proliferation was more pronounced when ΤΤ-100 was used at higher doses 144535.doc -169- 201023852 decreased. In summary, these experiments demonstrate that ΤΤ-100 inhibits Iressa resistant NSCLC cells. Example 19: In vivo TT-100 therapy inhibits the growth and activation of IGF_1R &amp; HER2 in breast tumors The MCNeuA isogenic breast cancer model was used to assess the effect of ττ_100 in vivo. MCNeuA cells were implanted into MMTVneu transgenic mice to induce tumor growth. Three times a week, 100 mg/kg TT_100 was administered by gavage (oral) or 37.5 mg/kg ΤΤ-100 was administered intraperitoneally. Tumor growth was monitored and tumor size was measured at various time points. On the 28th day, the tumor was removed 24 hours after the final ΤΤ-100 treatment. IGF-1R and HER2 phosphorylation were measured by ELISA. Figure 5 shows that TT-100 therapy via oral and intraperitoneal administration inhibits the growth of subcutaneous HER2 breast tumors in vivo. Figure 6 shows the receptor scalification of IGF-1R and HER2 compared to the vehicle-treated control group. ΤΤ_丨〇〇 therapy significantly inhibits HER2 and IGF-1R phosphorylation, and thus inhibits HER2 and IGF-1R activation in breast tumors in vivo. These experiments demonstrate the in vivo efficacy of ΤΤ-100 in inhibiting the growth and activation of ir and HER2 in breast tumors. Other aspects of the present application can be implemented or otherwise carried out without departing from the spirit or essential characteristics of the application. Accordingly, the invention is to be considered as illustrative and not restrictive [Simple Description] 144535.doc -170- 201023852 Figure 1 shows that NDGA (TT-IOO) directly inhibits purified IGF-1R and EGFR cheese with greater affinity than its effect on purified lipoxygenase (LOX). Amino acid kinase activity. Figure 2 shows that TT-100 inhibits Iressa-resistant NSCLC cells that exhibit an EGFR T790M mutation. Figure 3 shows that TT-100 has a synergistic effect with clinical concentration of Iressa in drug-resistant NSCLC cells. Figure 4 shows that TT-100 inhibits colony formation of Iressa resistant NSCLC cells. Figure 5 shows that TT-100 therapy inhibits the growth of HER2 breast tumors in vivo. Figure 6 shows that TT-100 therapy inhibits EGR and IGF-1R activation in breast tumors in vivo. 144535.doc 171 -

Claims (1)

201023852 VII. Patent Application Range: 1. A method for treating an individual's disease, wherein the individual has developed resistance to the treatment of one or more tyrosine kinase inhibitors, the method comprising administering an effective amount of an inhibitor of insulin-like growth factor A pharmaceutical compound of the -1 receptor (IGF-1R) and the tyrosine kinase activity of the epidermal growth factor receptor (EGFR). 2. As requested! A method wherein the individual has developed resistance to one or more egfr inhibitors or IGF-IR inhibitors. 3. The method of claim 1, wherein the disease is malignant, pre-malignant or benign sputum cancer. 4. The method of claim 3, wherein the cancer is selected from the group consisting of brain tumors, carcinomas, basal cell tumors (basaii〇Ina), basal cell carcinoma, teratoma, and retina Cell tumor, neuroblastoma, melanoma, choroidal melanoma, hyperplastic cutaneous fibrosarcoma, Merkel cell carcino-ma or Kaposi's sarcoma, seminoma, sarcoma , plasmacytoma, head and neck tumor, liver tumor, kidney tumor, renal cell tumor, squamous cell carcinoma, uterine tumor, endometrial tumor, bone tumor, prostate tumor, breast tumor, bladder tumor, pancreatic tumor, endometrium Tumor, squamous cell carcinoma, gastric tumor, glioma, pleomorphic glioblastoma, colorectal tumor, testicular tumor, colon tumor, rectal tumor, ovarian tumor, cervical tumor, cervical Tumor, central nervous system tumor, thyroid tumor, lung tumor, leukemia or lymphoma, multiple myeloma, cutaneous tumor, gynecological tumor, Huo Hodgkin's disease, small bowel cancer, endocrine system cancer, mesothelium 144535.doc 201023852 Tumor, urethral cancer, penile cancer, Gorlin's syndrome-related tumors, and tumors of unknown origin; Transfer. 5. The method of claim </ RTI> wherein the pharmaceutical compound comprises catechol butyl ketone of formula I, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate thereof, a metabolite thereof, and a mutual mutation thereof Structure or its prodrug: Wherein 1 and 112 are independently H, lower alkyl or lower fluorenyl; R3, r4, r5, r6, r1, R11, Ri2 and Rn are independently η or a lower carbon group; And &amp; independently are hydrazine, hydroxy, lower alkoxy or lower carboxy. 6. The method of claim 5, wherein the catechol butane is selected from the group consisting of 1,4-bis(3,4-dihydroxyphenyl)_2,3-didecylbutane; Bis(3,4-dihydroxyphenyl)butane; bis(a) cold dimethoxyphenyl) 2,3-dimethylbutane; 1,4-bis(3,4·diethoxy) Phenyl) 2,3-dimethylbutane, 1,4-bis(3,4-propoxyphenyl)_2,3-dimethylbutyring; (3,4-dihydroxyphenyl) · 4_(3,4,5-trihydroxyphenyl)butane; anthracene, 4 bis(3,4-ethyloxyphenyl)-2,3-dimethylbutane; 1,4-double ( 3,4-dipropoxyphenyl)-2,3-dimethylbutane; hydrazine, 'bis(3,4-dibutoxyphenyl)-2,3-didecylbutane ;14_bis(3,4-dipentyloxyphenyl 144535.doc -2- 201023852 dimercaptobutane; Μ·bis(3,4-di-p-pentyloxyphenyl)_2,3- Dimethylbutane; 1,4-bis(3,4-diopentylcarboxyphenyl)·2,3-dimethylbutane; 1-(3,4-dihydroxyphenyl)-4- Phenylbutane; 1_(3,4-dihydroxyphenyl)-4-(2,5--the basic base) butadiene, normal-wind guaiac acid (NDGA), tetra-anthracene-methyl NDGA; Tetraglycine NDGA; tetra-dimethylglycol-based NDGA or its salt; or triterpene-methyl NDGA; n-dihydroguaiare acid tetrapivalate; n-dihydroguaiare acid tetrapropionate and all its optical structures 7. The method of claim 5, wherein the catechol butane is n-dihydroguaiacol acid. 8. A method of treating cancer in a subject, wherein the individual has one or more tyrosine kinase inhibitors The treatment produces resistance, the method comprising administering an effective amount of a pharmaceutical composition capable of inhibiting the activity of tyrosine kinase of IGF-1R and EGFR, wherein the pharmaceutical composition comprises catechol butane. The method wherein the individual has developed resistance to one or more EGF R inhibitors or IGF-1R inhibitors. Φ 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 , lymphoma, leukemia, epithelial-based cancer, cerebral tumor, basaloma, basal cell eaixln〇ma, teratoma, retinoblastoma, neuroblastoma Choroidal melanoma, protuberous skin fiber Merkel cell carcinoma or Kaposi's sarcoma, seminoma, sarcoma plasma cell tumor, head and neck tumor, liver tumor, renal tumor, renal cell tumor, squamous cell carcinoma, uterine tumor, endometrial tumor, bone tumor , adenocarcinoma, breast tumor, bladder tumor, pancreatic tumor, intrauterine 144535.doc 201023852 Membrane tumor, squamous cell carcinoma, gastric tumor, glioma, pleomorphic glioblastoma, colorectal neoplasm, Testicular tumor, colon tumor, rectal tumor, ovarian tumor, cervical tumor, eye tumor, central nervous system tumor, thyroid tumor, lung tumor, leukemia or lymphoma, multiple myeloma, skin tumor, gynecological tumor, Hodgkin's Symptoms, small bowel cancer, endocrine system cancer, mesothelioma, urinary tract cancer, penile cancer, Golling's syndrome-related tumors and tumors of unknown origin; and their metastasis. 11. The method of claim 8 wherein the pharmaceutical composition comprises catechol butyrate of formula I, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate thereof, a metabolite thereof, and a mutual Isomers or their prodrugs: Rio, Rn, Ri2, and Rl3 are independently H or low. ^ and 尺2 are independently hydrazine, lower alkyl or lower fluorenyl; R3, R4, R5, r6, Rl 〇, RR and ampule are independently J-alkyl; and R7, h and Rg are independently Η , hydroxy, lower alkoxy or lower carboxy. 12. The method of claim 8, wherein the pharmaceutical composition comprises catechol butane of formula II, a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable solvent thereof. , its metabolite, its tautomer or its prodrug: 144535.doc 201023852 Wherein R5, R10, R6 and R13 are independently Η; when R·3 is Η, Rn is lower alkyl; or when 尺3 is lower alkyl, Ri 1 is Η; when R·4 is Η When R!2 is a lower alkyl group; or when &amp; is a lower alkyl group, ❿ Rl2 is Η; R7, Rs and R9 are both hydroxy and the other is oxime, and relative to the alkylene A substituent having one hydroxyl group at the 3 position and another hydroxyl group at the 4 position. 13. The method of claim 8, wherein the catechol butane is selected from the group consisting of 1,4-bis(3,4-dihydroxyphenyl)-2,3-dimethylbutane; I,4-bis(3,4-dihydroxyphenyl)butane; 14-bis, 4-dimethoxyphenyl 2,3-didecylbutane; 1,4-bis(3,4- Diethoxyphenyl)_2,3-dimethylbutane; 1,4-bis(3,4-dipropoxyphenyl)_2,3-didecylbutane; 1_ (3,4- Di-phenylphenyl)·4·(3,4,5-trisylphenyl)butanol; i,4-bis(3,4-diethyloxyphenyl)_2,3-dimethyl Butane; i, 4-bis(3,4-dipropoxyphenyl)-2,3-dimethylbutane; 1,4·bis(3,4-dibutoxyphenyl) -2,3-dimethylbutane; i,4-bis(3,4-dipentyloxyphenyl)-2,3-dimethylbutane; 1,4-bis(3,4- Di-p-pentyloxyphenyl)_2,3-didecylbutane; 1,4-bis(3,4-diopentylcarboxyphenyl)-2,3-didecylbutane; 1_( 3, 'dihydroxyphenyl)-4-phenylbutane; 1-(3,4-dihydroxyphenyl)-4-(2,5-monophenylene) butyl, n-dihydroguaiac acid ( NDGA), four-〇-曱144535.doc 201023852 base NDGA; four Aminoguanidine NDGA; tetrakis-dimethylglyoximeyl NDGA or a salt thereof; or tris-fluorene-methyl NDGA; n-dihydroguaiare acid tetrapivalate; n-dihydroguaiac acid tetrapropionate and All optical configurations. 14. The method of claim 8, wherein the catechol butane is n-dihydroguaiac acid. 15. The method of claim 8 wherein the catechol butane is administered in an amount selected from the group consisting of from about 5 mg/kg to about 375 mg/kg per dose; about 5 mg/kg per dose to About 250 mg/kg; about 5 mg/kg to about 200 mg/kg per dose; about 5 mg/kg to about 150 mg/kg per dose; about 5 mg/kg to about 1 mg/kg per dose; Each dose is from about 5 mg/kg to about 75 mg/kg, and from about 5 mg/kg to about 5 mg/kg per dose. 16. The method of claim 8, wherein the catechol butane is administered in an amount selected from the group consisting of: about 15 〇〇 11 ^ per day to about 2, 5 〇〇 吕 daily; From about 1,800 mg to about 23 mg per day; and about 2 mg per day. 17. The method of claim 8, further comprising administering one or more additional anti-cancer agents. 18. The method of claim 17, wherein the one or more additional anticancer agents are selected from the group consisting of an EGFR inhibitor, an IGF_1R inhibitor, a DNA disrupting agent, a topoisomerase (T〇P〇isomerase) inhibitor, and a mitotic inhibitor a group of people. 19. The method of claim 8, wherein the pharmaceutical composition is administered once per episode for a period of time, or once every two days for more than one duration. 144535.doc 201023852 20. A method for determining a disease therapy, comprising: (1) analyzing a sample obtained from an individual comprising measuring the content of IGF-1R and EGFR, and (ii) measuring IGF-1R and EGFR in the sample The content was compared with the amount in the control group; wherein an increase in the content of IGF-1R, EGFR or both compared to the control group indicates that the individual needs to be treated with a dual tyrosine kinase inhibitor. 21. The method of claim 20, wherein the EGFR expression is baseline content or © exceeds baseline content, and wherein the IGF-1R performance is baseline or exceeds baseline content. 22. The method of claim 21, wherein the EGFR expression is baseline and the IGF-1R performance is 2 or more times the baseline content; the IGF-1R performance is baseline and the EGFR performance is The baseline content is 2 times or more; or the IGF-1R performance is 2 times or more of the baseline content and the EGFR expression is 2 times or more of the baseline content. 23. The method of claim 20, wherein the dual tyrosine kinase inhibitor is catechol butane. 24. The method of claim 23, wherein the catechol butane is selected from the group consisting of 1,4-bis(3,4-dihydroxyphenyl)-2,3-didecylbutane; 1,4-bis(3,4-dihydroxyphenyl)butane; 1,4-bis(3,4-dimethoxyphenyl)-2,3-dimethylbutane; 1,4- Bis(3,4-diethoxyphenyl)-2,3-dimethylbutane; 1,4-bis(3,4-dipropyloxyphenyl)-2,3-dimethylbutyl Alkane; 1-(3,4-dihydroxyphenyl)-4-(3,4,5-trihydroxyphenyl)butane; 1,4-bis(3,4-diethyloxyphenyl) -2,3-dimethylbutane; 1,4-bis(3,4-dipropyl 144535.doc 201023852 ethoxylated phenyl)-2,3-dimercaptobutyrate; 1,4-double ( 3,4-dibutyloxyphenyl)-2,3-dimercaptobutane; 1,4-bis(3,4-dipentyloxyphenyl)_2,3-dimethylbutane; 1,4-bis(3,4-dipentyloxyphenyl)_2,3-didecylbutane; M-bis(3,4-di-p-pentylcarboxyphenyl)-2,3- Dimethyl butyrate; 1-(3,4-dihydroxyphenyl)-4-phenylbutane; 1-(3,4-dihydroxyphenyl)_4_(2,5-dihydroxyphenyl) Alkane, n-dihydroguaiac acid (NDGA), tetra-quinone-methyl NDGA; tetraglycol NDGA; tetra-dimercapto glycinate NDGA or its salt; or tri-O-methyl NDGA; n-dihydroguaiare acid tetrapivalate; n-dihydroguaiare acid tetrapropionate and all its optical structures type. The method of claim 23, wherein the catechol butane is administered in an amount selected from the group consisting of about 5 mg/kg to about 375 mg/kg per dose; about 5 mg/kg per dose. To about 250 mg/kg; about 5 mg/kg to about 200 mg/kg per dose; about 5 mg/kg to about 150 mg/kg per dose; about 5 mg/kg to about 100 mg/kg per dose; The dose is from about 5 mg/kg to about 75 mg/kg; and from about 5 mg/kg to about 50 mg/kg per dose. 26. The method of claim 23, wherein the catechol butane is administered in an amount selected from the group consisting of: about 1,5 〇〇 ^ ^ per day to about 2,50 〇 mg per day; From about 1,800 mg to about 2,300 mg per day; and about 2,000 mg per day. 27. The method of claim 23, wherein the catechol butane is administered once every 6 weeks for a period of time or every 2 days. 28. The method of claim 20, wherein the method of claim 20 further comprises administering one or more other anticancer agents. 144535.doc 201023852 29, wherein the method of claim 28, wherein the one or more other anticancer The agent is selected from the group consisting of an EGFR inhibitor, an IGF-1R inhibitor, a DNA disrupting agent, a hedgease inhibitor, and a mitotic inhibitor. 30. Selecting an individual to inhibit IGF_ 1R and EGF-R A method of treating a dual tyrosine kinase inhibitor of aminic acid kinase activity, wherein the individual is identified as having a level of IGF-1R, EGFR, or both that is twice the baseline or baseline level of the control. The method of claim 30, wherein the EGFR expression is a baseline And the IGF-1R performance is 2 times or more than the baseline content; the IGFir performance is the baseline content and the EGFR expression is 2 times or more of the baseline content, or the lGF_1R performance is the baseline 2 or more times the amount and the EGFR expression is 2 or more times the baseline content. 32. The method of claim 30, wherein the individual is resistant to treatment with at least one tyrosine kinase inhibitor 33. The method of claim 32, wherein the individual has developed resistance to one or more egf-R inhibitors or IGF-IR inhibitors. 34. The method of claim 30, wherein the dual tyrosine kinase inhibits The method of claim 34, wherein the catechol butane is selected from the group consisting of 1,4-bis(3,4-dihydroxyphenyl)-2 ,3-dimethylbutane; 1,4-bis(3,4-dihydroxyphenyl)butane; M-bis(3,4-dimethoxyphenyl)-2,3-dimethyl Butane; 1&gt;4•bis(3,4·diethoxyphenyl)_2,3-didecylbutane; 1,4-bis(3,4-dipropoxyphenyl)-2, 3-dimethylbutane; 1-(3,4-di-phenylphenyl)_4_(3,45-trihydroxyl Phenyl)butane; 14•double 144535.doc 201023852 (3,4-diethoxyoxyphenyl)-2,3-dimethylbutane; ι,4-bis(3,4-dipropyl) Oxyphenyl)-2,3-dimercaptobutane; 1,4-bis(3,4-dibutoxyphenyl)-2,3-dimercaptobutylate; 1,4-double (3,4-dipentyloxyphenyl)_2,3-dimethylbutane; 1,4-bis(3,4-dipentyloxyphenyl)_2,3-didecylbutane M-bis(3,4-di-pivalylcarboxyphenyl)-2,3-dimethylbutane; 1-(3,4-di-phenylphenyl)-4-phenylbutane; 1 -(3,4-di-phenylphenyl)_4_(2,5-di-propylphenyl)butane, n-dihydroguaiac acid (NDGA), tetra-anthracene-methyl NDGA; tetraglycine fluorenyl NDGA Tetra-dimercapto glycinate NDGA or a salt thereof; or tris-fluorene-methyl NDGA; n-dihydroguaiare acid tetrapivalate; n-dihydroguaiare acid tetrapropionate and all optical configurations thereof . 3. The method of claim 3, wherein the catechu is administered in an amount selected from the group consisting of about 5 mg/kg to about 375 mg/kg per dose; about 5 mg per dose per dose. Kg to about 250 mg/kg; about 5 mg/kg to about 200 mg/kg per dose; about 5 mg/kg to about 150 mg/kg per dose; about 5 mg/kg to about 100 mg/kg per dose; Each dose is from about 5 mg/kg to about 75 mg/kg; and from about 5 mg/kg to about 50 mg/kg per dose. 37. The method of claim 34, wherein the catechol butane is administered in an amount selected from the group consisting of from about 1,500 mg per day to about 2,500 mg per day; from about 1,800 mg per day to daily About 2,300 mg; and about 2,000 mg per ounce. 3. The method of claim 34, wherein the catechol butane is administered once every 6 days for a period of time or more than once every 2 days for a period of time. 39. The method of claim 30, which further comprises administering one or more additional anti-144535.doc •10·201023852 cancer agents. 40. The method of claim 39, wherein the one or more additional anticancer agents are selected from the group consisting of an EGFR inhibitor, an IGF-1R inhibitor, a DNA disrupting agent, a topoisomerase inhibitor, and a mitotic inhibitor. 144535.doc 11